Quinoline derivatives as tyrosine kinase inhibitors

ABSTRACT

The invention concerns quinoline derivatives of formula (I) wherein n is 0-3 and each R 4 , which may be the same or different, is a substituent such as halogeno, hydroxy, amino, nitro, trifluoromethyl, trifluoromethoxy, cyano or (1-6C)alkyl, or optionally substituted phenyl, phenoxy, anilino, N-(1-6C)alkylanilino, benzoyl or pyridyloxy; R 1  and R 2  is hydrogen or optionally substituted (1-6C)alkyl, (2-6C)alkenyl or (2-6C)alkynyl; or pharmaceutically-acceptable salts thereof; processes for their preparation, pharmaceutical compositions containing them and their use in the prevention or treatment of T cell mediated diseases or medical conditions

This application is the National Phase of International ApplicationPCT/GB00/00579 filed Feb. 18, 2000 which designated the U.S. and thatInternational Application was published under PCT Article 21(2) inEnglish.

This invention concerns certain novel quinoline derivatives whichpossess pharmacological properties of use in the treatment of autoimmunediseases or medical conditions, for example T cell mediated disease suchas transplant rejection or rheumatoid arthritis. The invention alsoconcerns processes for the manufacture of the quinoline derivatives ofthe invention, pharmaceutical compositions containing them and their usein therapeutic methods, for example by virtue of inhibition of T cellmediated disease.

A critical requirement of the immune system is the ability todifferentiate between “self” and “non-self” (i.e. foreign) antigens.This discrimination is required to enable the immune system to mount aresponse to foreign proteins such as those on the surface of pathogenswhilst maintaining tolerance to endogenous proteins and therebypreventing damage to normal tissues. An autoimmune disease results whenself-tolerance breaks down and the immune system reacts against tissuessuch as the joints in rheumatoid arthritis or nerve fibres in multiplesclerosis. Stimulation of the human immune response is dependent on therecognition of protein antigens by T cells. However T cells do notbecome activated by and respond to antigen alone but are only triggeredinto action when the antigen is complexed with major histocompatibilitycomplex (MHC) molecules on the surface of an antigen presenting cellsuch as a B cell, macrophage or dendritic cell.

Thus T cell activation requires the docking into the T cell receptor ofthe peptide/MHC complex expressed on an antigen presenting cell. Thisinteraction, which confers the antigen specificity to the T cellresponse, is essential for full activation of T lymphocytes. Subsequentto this docking, some of the earliest signal transduction events leadingto full T cell activation are mediated through the action of multipletyrosine-specific protein kinases (E. Hsi et al., J. Biol. Chem., 1989,264, 10836) including p56^(lck) and ZAP-70. The tyrosine kinasep56^(lck) is a lymphocyte specific member of the src family ofnon-receptor protein tyrosine kinases (J. D. Marth et al., Cell, 1985,43, 393). The enzyme is associated with the inner surface of the plasmamembrane where it binds to the T cell receptor associated glycoproteinsCD4 (in helper T cells) and CD8 (in cytotoxic or killer T cells) (C. E.Rudd et al., Proc. Natl. Acad. Sci. USA, 1988, 85, 5190 and M. A.Campbell et al, EMBO J, 1990, 9, 2125).

It is believed that p56^(lck) tyrosine kinase plays an essential role inT cell activation as, for example, the loss of p56^(lck) expression in ahuman Jurkat T cell line prevents the normal T cell response tostimulation of the T cell receptor (D. B. Straus et al., Cell, 1992, 70,585) and a deficiency in p56^(lck) expression causes severe immunedeficiency in humans (F. D. Goldman et al., J. Clin. Invest., 1998, 102,421).

Certain autoimmune conditions or diseases such as inflammatory diseases(for example rheumatoid arthritis, inflammatory bowel disease,glomerulonephritis and lung fibrosis), multiple sclerosis, psoriasis,hypersensitivity reactions of the skin, atherosclerosis, restenosis,allergic asthma and insulin-dependent diabetes are believed to beassociated with inappropriate T cell activation (see, for example, J. H.Hanke et al, Inflamm. Res., 1995, 44, 357). In addition the acuterejection of transplanted organs can also be interpreted as aconsequence of inappropriate T cell activation. Therefore, compoundswhich modulate T cell activation by way of inhibition of one or more ofthe multiple tyrosine-specific protein kinases which are involved in theearly signal transduction steps which lead to full T cell activation,for example by way of inhibition of p56^(lck) tyrosine kinase, areexpected to provide therapeutic agents for such pathological conditions.

Without wishing to imply that the compounds disclosed in the presentinvention possess pharmacological activity only by virtue of an effecton a single biological process, it is believed that the compoundsmodulate T cell activation by way of inhibition of one or more of themultiple tyrosine-specific protein kinases which are involved in theearly signal transduction steps which lead to full T cell activation,for example by way of inhibition of p56^(lck) tyrosine kinase.

In particular, the quinoline derivatives of the invention are expectedto be useful as immunoregulation or immunosuppressive agents for theprevention or treatment of organ rejection following transplant surgery.

Agents of this kind would offer therapy for transplant rejection andautoimmune diseases whilst avoiding toxicities associated with thecommonly used, less selective immunosuppressants. The leading agent forthe prevention or treatment of transplant rejection is cyclosporin Awhich, although effective, is often associated with side-effects such asrenal damage and hypertension which results in kidney failure in asubstantial number of patients. It is contemporary practice to treatrheumatoid arthritis initially with symptom relief agents such asNSAIDs, which do not have any beneficial effect on disease progressionand are often associated with unwanted side-effects. A rationally based,disease modifying agent, without such deleterious side-effects, wouldtherefore offer significant benefits in the prevention or treatment oftransplant rejection or autoimmune conditions such as rheumatoidarthritis.

The present invention is based, in particular, on the discovery that thequinoline derivatives of the invention modulate T cell activation by wayof inhibition of one or more of the multiple tyrosine-specific proteinkinases which are involved in the early signal transduction steps whichlead to full T cell activation. Accordingly compounds of the presentinvention possess higher inhibitory potency against particularnon-receptor tyrosine kinases such as p56^(lck) tyrosine kinase thanagainst other non-receptor tyrosine kinases or against receptor tyrosinekinases (RTKs) such as epidermal growth factor (EGF) RTK or vascularendothelial growth factor (VEGF) RTK. Nevertheless, whilst the quinolinederivatives of the present invention are generally potent inhibitors ofp56^(lck) tyrosine kinase, they do also, in general, possess weakeractivity against certain other tyrosine kinase enzymes. In particular,the quinoline derivatives of the present invention, in general, possesssome inhibitory activity against EGF RTK and, in general, they maypossess some weaker activity against VEGF RTK.

In general, the quinoline derivatives of the invention possesssufficient potency in inhibiting non-receptor tyrosine kinases such asp56^(lck) tyrosine kinase that they may be used in an amount sufficientto inhibit, for example, p56^(lck) tyrosine kinase whilst demonstratingreduced potency, preferably whilst demonstrating no significantactivity, against RTKs such as EGF RTK or VEGF RTK. Thus the quinolinederivatives of the invention can be used in the clinical management ofthose particular diseases which are sensitive to inhibition of suchnon-receptor tyrosine kinases, for example autoimmune diseases ormedical conditions, for example T cell mediated disease such astransplant rejection or rheumatoid arthritis.

Nevertheless, at appropriate higher doses, the quinoline derivatives ofthe present invention demonstrate pharmacologically useful inhibition ofother tyrosine kinase enzymes, for example of RTKs such as EGF RTKand/or VEGF RTK. In that event, the quinoline derivatives of theinvention are also useful in the treatment of further tyrosine kinasedependent diseases or conditions such as EGF-sensitive cancers andVEGF-sensitive angiogenesis.

It is disclosed in International Patent Application WO 96/09294 thatcertain quinoline and quinazoline derivatives may be useful as proteintyrosine kinase inhibitors. Whilst a few 4-benzyloxy- and4-phenoxy-quinazoline derivatives were disclosed, there was nodisclosure of any examples of 4-benzyloxy- or 4-phenoxy-quinolinederivatives.

It is disclosed in International Patent Application WO 97/03069 thatcertain quinoline and quinazoline derivatives may be useful as proteintyrosine kinase inhibitors. All of the disclosed examples were4-heteroarylaminoquinazoline derivatives and none of them were4-heteroarylmethoxy- or 4-heteroaryloxy-quinazoline derivatives.

It is disclosed in International Patent Application WO 98/13350 thatcertain quinoline derivatives may be useful in the production of anantiangiogenic and/or vascular permeability reducing effect. Whilstcertain 4-phenoxyquinoline derivatives are disclosed, there is nodisclosure of any such compounds which possess a carboxy,alkoxycarbonyl, carbamoyl or N-alkylcarbamoyl substituent on thequinoline ring.

It is disclosed in International Patent Application WO 98/43960 thatcertain 3-cyanoquinoline derivatives may be useful as protein tyrosinekinase inhibitors. Almost all of the 398 disclosed examples were3-cyano-4-anilinoquinoline or 3-cyano-4-benzylaminoquinolinederivatives. There was the disclosure of a single3-cyano-4-phenoxyquinoline derivative but there was no disclosure of anysuch compounds which possess a carbamoyl or N-alkylcarbamoyl substituenton the quinoline ring.

According to one aspect of the invention there is provided a quinolinederivative of the Formula I

wherein

n is 0, 1, 2 or 3 and each R⁴, which may be the same or different, ishalogeno, hydroxy, amino, nitro, trifluoromethyl, trifluoromethoxy,cyano, (1-6C)alkyl, (2-6C)alkenyl, (2-6C)alkynyl, (1-6C)alkoxy,(1-6C)alkylamino, di-[(1-6C)alkyl]amino, (2-6C)alkanoylamino,(1-6C)alkylthio, (1-6C)alkylsulphinyl, (1-6C)alkylsulphonyl,pyrrolidin-1-yl, piperidino, morpholino, piperazin-1-yl or4-(1-6C)alkylpiperazin-1-yl, and any CH₂ or CH₃ group in a R⁴ groupoptionally bears on each such CH₂ or CH₃ group a substituent selectedfrom halogeno, hydroxy, amino, cyano, (1-6C)alkyl, (1-6C)alkoxy,(1-6C)alkylamino, di-[(1-6C)alkyl]amino and (2-6C)alkanoylamino, or R⁴is phenyl, phenoxy, anilino, N-(1-6C)alkylanilino, benzoyl, phenylthio,phenylsulphinyl, phenylsulphonyl, benzyl, pyridyl or pyridyloxy and thephenyl or pyridyl group in any of the 11 last-named substituents isoptionally substituted with 1, 2 or 3 substituents, which may be thesame or different, selected from halogeno, hydroxy, amino, nitro,trifluoromethyl, trifluoromethoxy, cyano, (1-6C)alkyl, (2-6C)alkenyl,(2-6C)alkynyl, (1-6C)alkoxy, (1-6C)alkylamino, di-[(1-6C)alkyl]amino and(2-6C)alkanoylamino, or (R⁴)_(n) is a (1-3C)alkylenedioxy substituent;

R¹ is hydrogen, (1-6C)alkyl, (2-6C)alkenyl or (2-6C)alkynyl;

R² is hydrogen, (1-6C)alkyl, (2-6C)alkenyl or (2-6C)alkynyl;

and wherein any CH₂ or CH₃ group in an R¹ or R² group optionally bearson each such CH₂ or CH₃ group a substituent selected from halogeno,hydroxy, amino, cyano, carbamoyl, sulphamoyl, (1-6C)alkoxy,(1-6C)alkylamino, di-[(1-6C)alkyl]amino, (2-6C)alkanoylamino,(1-6C)alkylthio, (1-6C)alkylsulphinyl, (1-6C)alkylsulphonyl,N-(1-6C)alkylcarbamoyl, N,N-di-[(1-6C)alkyl]carbamoyl,N-(1-6C)alkylsulphamoyl and N,N-di-[(1-6C)alkyl]sulphamoyl, or asubstituent selected from aryl, aryloxy, arylamino,N-(1-6C)alkyl-arylamino, aryl-(1-6C)alkoxy, aryl-(1-6C)alkylamino,N-(1-6C)alkyl-aryl-(1-6C)alkylamino, aroylamino, N-arylcarbamoyl,aryl-(2-6C)alkanoylamino and N-[aryl-(1-6C)alkyl]carbamoyl, or asubstituent selected from (3-7C)cycloalkyl, (3-7C)cycloalkyloxy,(3-7C)cycloalkylamino, N-(1-6C)alkyl-(3-7C)cycloalkylamino,(3-7C)cycloalkyl-(1-6C)alkoxy, (3-7C)cycloalkyl-(1-6C)alkylamino,N-(1-6C)alkyl-(3-7C)cycloalkyl-(1-6C)alkylamino,(3-7C)cycloalkylcarbonylamino, N-[(3-7C)cycloalkyl]carbamoyl,(3-7C)cycloalkyl-(2-6C)alkanoylamino andN-[(3-7C)cycloalkyl-(1-6C)alkyl]carbamoyl, or a substituent selectedfrom heteroaryl, heteroaryloxy, heteroarylamino,N-(1-6C)alkyl-heteroarylamino, heteroaryl-(1-6C)alkoxy,heteroaryl-(1-6C)alkylamino, N-(1-6C)alkyl-heteroaryl-(1-6C)alkylamino,heteroarylcarbonylamino, N-heteroarylcarbamoyl,heteroaryl-(2-6C)alkanoylamino and N-[heteroaryl-(1-6C)alkyl]carbamoyl,or a substituent selected from heterocyclyl, heterocyclyloxy,heterocyclylamino, N-(1-6C)alkyl-heterocyclylamino,heterocyclyl-(1-6C)alkoxy, heterocyclyl-(1-6C)alkylamino,N-(1-6C)alkyl-heterocyclyl-(1-6C)alkylamino, heterocyclylcarbonylamino,N-heterocyclylcarbamoyl, heterocyclyl-(2-6C)alkanoylamino andN-[heterocyclyl-(1-6C)alkyl]carbamoyl, and wherein any aryl,(3-7C)cycloalkyl, heteroaryl or heterocyclyl group in a substituent onR¹ or R² optionally bears 1, 2 or 3 substituents, which may be the sameor different, selected from halogeno, hydroxy, amino, nitro,trifluoromethyl, trifluoromethoxy, cyano, (1-6C)alkyl, (2-6C)alkenyl,(2-6C)alkynyl, (1-6C)alkoxy, (1-6C)alkylamino, di-[(1-6C)alkyl]amino and(2-6C)alkanoylamino and any (3-7C)cycloalkyl or heterocyclyl group on aR¹ or R² group optionally bears 1 or 2 oxo substituents; and

R³ is hydrogen, halogeno, hydroxy, amino, (1-6C)alkyl, (1-6C)alkoxy,(1-6C)alkylamino, di-[(1-6C)alkyl]amino or (2-6C)alkanoylamino;

or a pharmaceutically-acceptable salt thereof.

In this specification the generic term “alkyl” includes bothstraight-chain and branched-chain alkyl groups. However references toindividual alkyl groups such as “propyl” are specific for thestraight-chain version only and references to individual branched-chainalkyl groups such as “isopropyl” are specific for the branched-chainversion only. An analogous convention applies to other generic terms.

It is to be understood that, insofar as certain of the compounds ofFormula I defined above may exist in optically active or racemic formsby virtue of one or more asymmetric carbon atoms, the invention includesin its definition any such optically active or racemic form whichpossesses the above-mentioned activity. The synthesis of opticallyactive forms may be carried out by standard techniques of organicchemistry well known in the art, for example by synthesis from opticallyactive starting materials or by resolution of a racemic form. Similarly,the above-mentioned activity may be evaluated using the standardlaboratory techniques referred to hereinafter.

Suitable values for the generic radicals referred to above include thoseset out below.

A suitable value for a substituent on R¹ or R² when it is aryl or forthe aryl group within a substituent on R¹ or R² is, for example, phenylor naphthyl, preferably phenyl.

A suitable value for a substituent on R¹ or R² when it is(3-7C)cycloalkyl or for the (3-7C)cycloalkyl group within a substituenton R¹ or R² is, for example, cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl or cycloheptyl, preferably cyclopentyl or cyclohexyl. Asuitable value for such a group which bears 1 or 2 oxo substituents is,for example, 2-oxocyclopentyl, 2-oxocyclohexyl or 4-oxocyclohexyl.

A suitable value for a substituent on R¹ or R² when it is heteroaryl orfor the heteroaryl group within a substituent on R₁ or R² is, forexample, an aromatic 5- or 6-membered monocyclic ring or a 9- or10-membered bicyclic ring with up to five ring heteroatoms selected fromoxygen, nitrogen and sulphur, for example furyl, pyrrolyl, thienyl,oxazolyl, isoxazolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl,oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, pyridyl, pyridazinyl,pyrimidazinyl, pyrazinyl, 1,3,5-triazenyl, benzofuranyl, indolyl,benzothienyl, benzoxazolyl, benzimidazolyl, benzothiazolyl, indazolyl,benzofurazanyl, quinolyl, isoquinolyl, quinazolinyl, quinoxalinyl,cinnolinyl or naphthyridinyl, preferably furyl, thienyl, oxazolyl,isoxazolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, pyridyl,pyridazinyl, pyrimidinyl, pyrazinyl, benzofuranyl, indolyl,benzothienyl, benzoxazolyl, benzimidazolyl, benzothiazolyl, indazolyl,benzofurazanyl, quinolyl, isoquinolyl, quinazolinyl, quinoxalinyl ornaphthyridinyl.

A suitable value for a substituent on R₁ or R² when it is heterocyclylor for the heterocyclyl group within a substituent on R¹ and R² is, forexample, a non-aromatic saturated or partially saturated 3 to 10membered monocyclic or bicyclic ring with up to five heteroatomsselected from oxygen, nitrogen and sulphur, for example oxiranyl,oxetanyl, tetrahydrofuranyl, pyrrolinyl, pyrrolidinyl, imidazolinyl,imidazolidinyl, thiazolinyl, thiazolidinyl, pyrazolinyl, pyrazolidinyl,morpholinyl, piperidinyl, piperazinyl, homopiperazinyl,dihydropyridinyl, tetrahydropyridinyl, dihydropyrimidinyl,tetrahydropyrimidinyl, indolinyl, isoindolinyl,2,3-dihydrobenzimidazolyl, 1,2,3,4-tetrahydroquinolinyl or chromanyl,preferably pyrrolidin-1-yl, imidazolidin-1-yl, thiazolidin-3-yl,morpholino, piperidino, piperazin-1-yl or homopiperazin-1-yl. A suitablevalue for such a group which bears 1 or 2 oxo substituents is, forexample, 2-oxopyrrolidinyl, 2-oxoimidazolidinyl, 2-oxopiperidinyl,2,5-dioxopyrrolidinyl, 2,4-dioxoimidazolidinyl, 2,5-dioxoimidazolidinyl,2,4-dioxothiazolidinyl or 2,6-dioxopiperidinyl.

Suitable values for R¹, R², R³ or R⁴, or for various substituents on R¹,R² or R⁴, or within a substituent on R₁ or R² include:

for halogeno fluoro, chloro, bromo and iodo;

for (1-6C)alkyl: methyl, ethyl, propyl, isopropyl and tert-butyl;

for (2-6C)alkenyl: vinyl, allyl and but-2-enyl;

for (2-6C)alkynyl: ethynyl, 2-propynyl and but-2-ynyl;

for (1-6C)alkoxy: methoxy, ethoxy, propoxy, isopropoxy and butoxy;

for (1-6C)alkylamino: methylamino, ethylamino, propylamino,isopropylamino and butylamino;

for di-[(1-6C)alkyl]amino: dimethylamino, diethylamino,N-ethyl-N-methylamino and diisopropylamino;

for (2-6C)alkanoylamino: acetamido and propionamido;

for (1-6C)alkylthio: methylthio, ethylthio and propylthio;

for (1-6C)alkylsulphinyl: methylsuiphinyl and ethylsulphinyl;

for (1-6C)alkylsulphonyl: methylsulphonyl and ethylsulphonyl;

for 4-(1-6C)alkylpiperazin-1-yl: 4-methylpiperazin-1-yl;

for N-(1-6C)alkylanilino: N-methylanilino and N-ethylanilino;

for pyridyl: 2-pyridyl, 3-pyridyl and 4-pyridyl;

for pyridyloxy: 2-pyridyloxy, 3-pyridyloxy and 4-pyridyloxy;

for N-(1-6C)alkylcarbamoyl: N-methylcarbamoyl and N-ethylcarbamoyl;

for N,N-di-[(1-6C)alkyl]carbamoyl: N,N-dimethylcarbamoyl andN,N-diethylcarbamoyl;

for N-(1-6C)alkylsulphamoyl: N-methylsulphamoyl and N-propylsulphamoyl;for N,N-di-[(1-6C)alkyl]sulphamoyl: N,N-dimethylsulphamoyl andN,N-dipropylsulphamoyl.

A suitable value for (R⁴)_(n) when it is (1-3C)alkylenedioxy is, forexample, methylenedioxy or ethylenedioxy and the oxygen atoms thereofoccupy adjacent positions on the phenyl ring.

When, as defined hereinbefore, any CH₂ or CH₃ group in an R⁴ groupoptionally bears on each such CH₂ or CH₃ group a substituent as definedhereinbefore, suitable R⁴ groups so formed include, for example, a(1-6C)alkylamino-(1-6C)alkoxy group such as 2-methylaminoethoxy and3-methylaminopropoxy, a di-[(1-6C)alkyl]amino-(1-6C)alkoxy group such as2-dimethylaminoethoxy and 3-dimethylaminopropoxy, a(1-6C)alkylamino-(1-6C)alkylamino group such as 2-methylaminoethylaminoand 3-methylaminopropylamino, a di-[(1-6C)alkyl]amino-(1-6C)alkylaminogroup such as 2-dimethylaminoethylamino and 3-dimethylaminopropylamino,and a (1-6C)alkoxy-(1-6C)alkyl group such as 2-methoxyethyl.

Suitable values for substituents on R¹ or R² include:

for N-(1-6C)alkyl-heteroarylamino: N-methylheteroarylamino;

for heteroaryl-(1-6C)alkoxy: heteroarylmethoxy and 2-heteroarylethoxy;

for heteroaryl-(1-6C)alkylamino: heteroarylmethylamino,2-heteroarylethylamino and 3-heteroarylpropylamino;

for N-(1-6C)alkyl-heteroaryl-(1-6C)alkylamino:N-methylheteroarylmetlhylamino and N-methyl-2-heteroarylethylamino;

for heteroaryl-(2-6C)alkanoylamino: heteroarylacetamido and3-heteroarylpropionamido;

for N-[heteroaryl-(1-6C)alkyl]carbamoyl: N-heteroarylmethylcarbamoyl andN-(2-heteroarylethyl)carbamoyl.

The invention comprises corresponding suitable values for substituentson R¹ or R² when, for example, rather than a heteroaryl-(1-6C)alkoxygroup, an aryl-(1-6C)alkoxy, (3-7C)cycloalkyl-(1-6C)alkoxy orheterocyclyl-(1-6C)alkoxy group is present.

When, as defined hereinbefore, any CH₂ or CH₃ group in an R¹ or R² groupoptionally bears on each such CH₂ or CH₃ group a substituent as definedhereinbefore, suitable R¹ and R² groups so formed include, for example,aryl-(1-6C)alkyl groups such as 2-phenethyl and 3-phenylpropyl,aroylamino-(1-6C)alkyl groups such as 3-benzamidopropyl,(3-7C)cyclopropyl-(1-6C)alkyl groups such as 3-cyclopentylpropyl,N-[(3-7C)cycloalkyl]-carbamoyl-(1-6C)alkyl groups such as3-(N-cyclohexylcarbamoyl)propyl, heteroaryl-(1-6C)alkyl groups such as2-(2-pyridyl)ethyl, heteroarylcarbonylamino-(1-6C)alkyl groups such as3-(2-pyridylcarbonylamino)propyl, heterocyclyl-(1-6C)alkyl groups suchas 2-pyrrolidin-1-ylethyl, 3-morpholinopropyl and2-hydroxy-3-piperidinopropyl, substituted (1-6C)alkoxy-(1-6C)alkylgroups such as 2-methoxyethyl, substituted (1-6C)alkylamino-(1-6C)alkylgroups such as 2-methylaminoethyl, substituteddi-[(1-6C)alkyl]amino-(1-6C)alkyl groups such as 2-dimethylaminoethyland substituted (1-6C)alkylthio-(1-6C)alkyl groups such as2-methylthioethyl.

A suitable pharmaceutically-acceptable salt of a compound of the FormulaI is, for example, an acid-addition salt of a compound of the Formula Iwhich is sufficiently basic, for example an acid-addition salt with aninorganic or organic acid such as hydrochloric, hydrobromic, sulphuric,trifluoroacetic, citric or maleic acid; or, for example, a salt of acompound of the Formula I which is sufficiently acidic, for example analkali or alkaline earth metal salt such as a calcium or magnesium salt,or an ammonium salt, or a salt with an organic base such as methylamine,dimethylamine, trimethylamine, piperidine, morpholine ortris-(2-hydroxyethyl)amine.

According to a further aspect of the invention there is provided aquinoline derivative of the Formula I

wherein

n is 0, 1, 2 or 3 and R⁴ is halogeno, hydroxy, amino, nitro,trifluoromethyl, trifluoromethoxy, cyano, (1-6C)alkyl, (2-6C)alkenyl,(2-6C)alkynyl, (1-6C)alkoxy, (1-6C)alkylamino, di-[(1-6C)alkyl]amino,(2-6C)alkanoylamino, phenyl, phenoxy, anilino, phenylthio,phenylsulphinyl, phenylsulphonyl or benzyl and the phenyl group in anyof the 7 last-named substituents is optionally substituted with 1, 2 or3 substituents selected from halogeno, hydroxy, amino, nitro,trifluoromethyl, trifluoromethoxy, cyano, (1-6C)alkyl, (2-6C)alkenyl,(2-6C)alkynyl, (1-6C)alkoxy, (1-6C)alkylamino, di-[(1-6C)alkyl]amino and(2-6C)alkanoylamino, or (R⁴)_(n) is a (1-3C)alkylenedioxy substituent;

R¹ is hydrogen, (1-6C)alkyl, (2-6C)alkenyl or (2-6C)alkynyl;

R² is hydrogen, (1-6C)alkyl, (2-6C)alkenyl or (2-6C)alkynyl;

and wherein any CH₂ or CH₃ group in an R¹ or R² group optionally bearson each such CH₂ or CH₃ group a substituent selected from halogeno,hydroxy, amino, cyano, (1-6C)alkoxy, (1-6C)alkylamino,di-[(1-6C)alkyl]amino and (2-6C)alkanoylamino, or a substituent selectedfrom aryl, aryloxy, arylamino, N-(1-6C)alkyl-arylamino,aryl-(1-6C)alkoxy, aryl-(1-6C)alkylamino,N-(1-6C)alkyl-aryl-(1-6C)alkylamino, aroylamino, N-arylcarbamoyl,aryl-(2-6C)alkanoylamino and N-[aryl-(1-6C)alkyl]carbamoyl, or asubstituent selected from (3-7C)cycloalkyl, (3-7C)cycloalkyloxy,(3-7C)cycloalkylamino, N-(1-6C)alkyl-(3-7C)cycloalkylamino,(3-7C)cycloalkyl-(1-6C)alkoxy, (3-7C)cycloalkyl-(1-6C)alkylamino,N-(1-6C)alkyl-(3-7C)cycloalkyl-(1-6C)alkylamino,(3-7C)cycloalkylcarbonylamino, N-[(3-7C)cycloalkyl]carbamoyl,(3-7C)cycloalkyl-(2-6C)alkanoylamino andN-[(3-7C)cycloalkyl-(1-6C)alkyl]carbamoyl, or a substituent selectedfrom heteroaryl, heteroaryloxy, heteroarylamino,N-(1-6C)alkyl-heteroarylamino, heteroaryl-(1-6C)alkoxy,heteroaryl-(1-6C)alkylamino, N-(1-6C)alkyl-heteroaryl-(1-6C)alkylamino,heteroarylcarbonylamino, N-heteroarylcarbamoyl,heteroaryl-(2-6C)alkanoylamino and N-[heteroaryl-(1-6C)alkyl]carbamoyl,or a substituent selected from heterocyclyl, heterocyclyloxy,heterocyclylamino, N-(1-6C)alkyl-heterocyclylamino,heterocyclyl-(1-6C)alkoxy, heterocyclyl-(1-6C)alkylamino,N-(1-6C)alkyl-heterocyclyl-(1-6C)alkylamino, heterocyclylcarbonylamino,N-heterocyclylcarbamoyl, heterocyclyl-(2-6C)alkanoylamino andN-[heterocyclyl-(1-6C)alkyl]carbamoyl, and wherein any aryl,(3-7C)cycloalkyl, heteroaryl or heterocyclyl group in a substituent onR¹ or R² optionally bears 1, 2 or 3 substituents selected from halogeno,hydroxy, amino, nitro, trifluoromethyl, trifluoromethoxy, cyano,(1-6C)alkyl, (2-6C)alkenyl, (2-6C)alkynyl, (1-6C)alkoxy,(1-6C)alkylamino, di-[(1-6C)alkyl]amino, and (2-6C)alkanoylamino and any(3-7C)cycloalkyl or heterocyclyl group on a R¹ or R² group optionallybears 1 or 2 oxo substituents; and

R³ is hydrogen, halogeno, hydroxy, amino, (1-6C)alkyl, (1-6C)alkoxy,(1-6C)alkylamino, di-[(1-6C)alkyl]amino or (2-6C)alkanoylamino;

or a pharmaceutically-acceptable salt thereof.

Particular novel compounds of the invention include, for example,quinoline derivatives of the Formula I, or pharmaceutically-acceptablesalts thereof, wherein, unless otherwise stated, each of n, R¹, R², R³and R⁴ has any of the meanings defined hereinbefore or in this sectionconcerning particular compounds of the invention:

(a) when R² is hydrogen, R¹ has one of the meanings defined hereinbeforeother than hydrogen;

(b) R² is hydrogen and R¹ is (1-6C)alkyl wherein 1 or 2 CH₂ or CH₃groups bears a substituent as defined hereinbefore;

(c) R² is hydrogen and R¹ is (1-6C)alkyl which bears 1 or 2 substituentsselected from hydroxy, amino, cyano, (1-6C)alkoxy, (1-6C)alkylamino,di-[(1-6C)alkyl]amino, (2-6C)alkanoylamino, phenyl, phenoxy,phenyl-(1-6C)alkoxy, benzamido, N-phenylcarbamoyl, (3-7C)cycloalkyl,(3-7C)cycloalkyloxy, (3-7C)cycloalkyl-(1-6C)alkoxy,(3-7C)cycloalkylcarbonylamino, N-[(3-7C)cycloalkyl]carbamoyl,heteroaryl, heteroaryloxy, heteroaryl-(1-6C)alkoxy,heteroarylcarbonylamino, N-heteroarylcarbamoyl, heterocyclyl,heterocyclyloxy, heterocyclyl-(1-6C)alkoxy, heterocyclylcarbonylaminoand N-heterocyclylcarbamoyl and wherein any phenyl, heteroaryl orheterocyclyl group in a R¹ substituent optionally bears 1 or 2substituents selected from halogeno, hydroxy, amino, trifluoromethyl,cyano, (1-6C)alkyl, (1-6C)alkoxy, (1-6C)alkylamino,di-[(1-6C)alkyl]amino and (2-6C)alkanoylamino and wherein any(3-7C)cycloalkyl or heterocyclyl group in a R¹ substituent optionallybears 1 or 2 oxo substituents;

(d) R² is hydrogen and R¹ is (1-6C)alkyl which bears 1 or 2 substituentsselected from hydroxy, amino, cyano, (1-6C)alkoxy, (1-6C)alkylamino,di-[(1-6C)alkyl]amino, (2-6C)alkanoylamino, phenyl, furyl, thienyl,pyrrolyl, imidazolyl, pyrazolyl, pyridyl, pyrimidinyl,furylcarbonylamino, thienylcarbonylamino, pyridylcarbonylamino,pyrrolidinyl, imidazolidinyl, morpholinyl, piperidinyl, piperazinyl andhomopiperazinyl and wherein any of the 17 last-named substituents on R¹optionally bears 1 or 2 further substituents selected from halogeno,hydroxy, amino, trifluoromethyl, cyano, (1-6C)alkyl, (1-6C)alkoxy,(1-6C)alkylamino, di-[(1-6C)alkyl]amino and (2-6C)alkanoylamino andwherein any of the 6 heterocyclic substituents on R¹ (from pyrrolidinylto homopiperazinyl) optionally bears 1 or 2 oxo substituents; and

(e) R³ is (1-6C)alkoxy.

A preferred compound of the invention is a quinoline derivative of theFormula I wherein n is 1, 2 or 3 and each R⁴ group is independentlyselected from fluoro, chloro, bromo, hydroxy, amino, trifluoromethyl,methyl, methoxy, methylamino, dimethylamino, acetamido, phenyl andphenoxy and wherein said 2 last-named substituents optionally bear 1, 2or 3 substituents selected from fluoro, chloro, bromo, methyl andmethoxy;

R² is hydrogen;

R¹ is ethyl, propyl or butyl which bears 1 or 2 substituents selectedfrom hydroxy, amino, cyano, methoxy, ethoxy, methylamino, ethylamino,dimethylamino, diethylamino, acetamido, phenyl, imidazolyl, pyridyl,pyrrolidinyl, imidazolidinyl, morpholinyl, piperidinyl and piperazinyland wherein any of the 8 last-named substituents on R¹ optionally bears1 or 2 further substituents selected from fluoro, chloro, bromo,hydroxy, amino, trifluoromethyl, cyano, methyl, methoxy, methylamino,dimethylamino and acetamido and wherein any of the pyrrolidinyl,imidazolidinyl, morpholinyl, piperidinyl and piperazinyl substituents onR¹ optionally bears 1 or 2 oxo substituents; and

R³ is methoxy;

or a pharmaceutically-acceptable salt thereof.

A further preferred compound of the invention is a quinoline derivativeof the Formula I

wherein

n is 1, 2 or 3 and each R⁴ group is independently selected from fluoro,chloro, bromo, hydroxy, amino, trifluoromethyl, cyano, methyl, ethyl,methoxy, ethoxy, methylamino, ethylamino, propylamino, butylamino,dimethylamino, diethylamino, acetamido, methylthio, piperidin-1-yl,piperidino, morpholino, piperazin-1-yl, 4-methylpiperazin-1-yl, phenyl,phenoxy, anilino, N-methylanilino, benzoyl, phenylthio, benzyl,4-pyridyl and 4-pyridyloxy;

R² is hydrogen;

R¹ is ethyl, propyl or butyl which bears a substituent selected fromhydroxy, amino, methoxy, methylamino, dimethylamino, acetamido,methylthio, methylsulphinyl, methylsulphonyl, N-methylcarbamoyl,N,N-dimethylcarbamoyl, N-methylsulphamoyl, N-ethylsulphamoyl,N-propylsulphamoyl, N,N-dimethylsulphamoyl, 4-chlorophenyl,4-aminophenyl, 4-methoxyphenyl, 1-imidazolyl, 2-imidazolyl, 2-pyridyl,pyrrolidin-1-yl, 2-oxopyrrolidin-1-yl, 2-oxoimidazolidin-1-yl,2,4-dioxoimidazolidin-1-yl, 5-methyl-2,4-dioxothiazolidin-3-yl,piperidino, 2,6-dioxopiperidin-1-yl, morpholino, piperazin-1-yl and4-methylpiperazin-1-yl;

and R³ is methoxy;

or a pharmaceutically-acceptable salt thereof.

A further preferred compound of the invention is a quinoline derivativeof the Formula I

wherein

n is 1 or 2 and each R⁴ group is independently selected from fluoro,chloro, dimethylamino, acetamido, phenyl and phenoxy;

R² is hydrogen;

R¹ is ethyl or propyl which bears a substituent selected from4-chlorophenyl, 4-aminophenyl, 4-methoxyphenyl, 2-pyridyl,2-oxoimidazolidin-1-yl and morpholino; and

R³ is methoxy;

or a pharmaceutically-acceptable salt thereof

A particular preferred compound of the invention is, for example, aquinoline derivative of the Formula I selected from:

4-(4-chloro-2-fluorophenoxy)-7-methoxy-N-(3-morpholinopropyl)quinoline-6-carboxamide,4-(3,4-dichlorophenoxy)-7-methoxy-N-(3-morpholinopropyl)quinoline-6-carboxamide,4-(4-chloro-2-fluorophenoxy)-N-[2-(2-oxoimidazolidin-1-yl)ethyl]-7-methoxyquinoline-6-carboxamideand

7-methoxy-N-(3-morpholinopropyl)-4-(4-phenoxyphenoxy)quinoline-6-carboxamide;

or a pharmaceutically-acceptable salt thereof.

A quinoline derivative of the Formula I, or apharmaceutically-acceptable salt thereof, may be prepared by any processknown to be applicable to the preparation of chemically-relatedcompounds. Such processes, when used to prepare a quinoline derivativeof the Formula I are provided as a further feature of the invention andare illustrated by the following representative process variants inwhich, unless otherwise stated, R¹, R², R³, R⁴ and n have any of themeanings defined hereinbefore. Necessary starting materials may beobtained by standard procedures of organic chemistry. The preparation ofsuch starting materials is described in conjunction with the followingrepresentative process variants and within the accompanying Examples.Alternatively necessary starting materials are obtainable by analogousprocedures to those illustrated which are within the ordinary skill ofan organic chemist.

(a) The reaction, conveniently in the presence of a suitable base, of aquinoline of the Formula II

wherein Z is a displaceable group and R¹, R², R³ and m have any of themeanings defined hereinbefore except that any functional group isprotected if necessary, with a phenol of the Formula III

wherein R⁴ and n have any of the meanings defined hereinbefore exceptthat any functional group is protected if necessary, whereafter anyprotecting group that is present is removed by conventional means.

A suitable base is, for example, an organic amine base such as, forexample, pyridine, 2,6-lutidine, collidine, 4-dimethylaminopyridine,triethylamine, morpholine, N-methylmorpholine ordiazabicyclo[5.4.0]undec-7-ene, or, for example, an alkali or alkalineearth metal carbonate, alkoxide or hydroxide, for example sodiumcarbonate, potassium carbonate, calcium carbonate, sodium ethoxide,potassium tert-butoxide, sodium hydroxide or potassium hydroxide, or,for example, an alkali metal hydride, for example sodium hydride orpotassium hydride, or an organometallic base such as an alkyl-lithium,for example n-butyl-lithium or a dialkylamino-lithium, for examplelithium di-isopropylamide.

A suitable displaceable group Z is, for example, a halogeno, alkoxy,aryloxy or sulphonyloxy group, for example a chloro, bromo, methoxy,phenoxy, methanesulphonyloxy or toluene-4-sulphonyloxy group. Thereaction is conveniently carried out in the presence of a suitable inertsolvent or diluent, for example an alkanol or ester such as methanol,ethanol, isopropanol or ethyl acetate, a halogenated solvent such asmethylene chloride, chloroform or carbon tetrachloride, an ether such astetrahydrofuran or 1,4-dioxan, an aromatic solvent such as toluene, or adipolar aprotic solvent such an N,N-dimethylformamide,N,N-dimethylacetamide, N-methylpyrrolidin-2-one or dimethylsulphoxide.The reaction is conveniently carried out at a temperature in the range,for example, 10 to 250° C., preferably in the range 50 to 150° C.

The quinoline derivative of the Formula I may be obtained from thisprocess in the form of the free base or alternatively it may be obtainedin the form of a salt with the acid of the formula H-Z wherein Z has themeaning defined hereinbefore. When it is desired to obtain the free basefrom the salt, the salt may be treated with a suitable base, forexample, an organic amine base such as, for example, pyridine,2,6-lutidine, collidine, 4-dimethylaminopyridine, triethylamine,morpholine, N-methylmorpholine or 1,8-diazabicyclo[5.4.0]undec-7-ene,or, for example, an alkali or alkaline earth metal carbonate orhydroxide, for example sodium carbonate, potassium carbonate, calciumcarbonate, sodium hydroxide or potassium hydroxide.

Protecting groups may in general be chosen from any of the groupsdescribed in the literature or known to the skilled chemist asappropriate for the protection of the group in question and may beintroduced by conventional methods. Protecting groups may be removed byany convenient method as described in the literature or known to theskilled chemist as appropriate for the removal of the protecting groupin question, such methods being chosen so as to effect removal of theprotecting group with minimum disturbance of groups elsewhere in themolecule.

Specific examples of protecting groups are given below for the sake ofconvenience, in which “lower”, as in, for example, lower alkyl,signifies that the group to which it is applied preferably has 1-4carbon atoms. It will be understood that these examples are notexhaustive. Where specific examples of methods for the removal ofprotecting groups are given below these are similarly not exhaustive.The use of protecting groups and methods of deprotection notspecifically mentioned are, of course, within the scope of theinvention.

A carboxy protecting group may be the residue of an ester-formingaliphatic or arylaliphatic alcohol or of an ester-forming silanol (thesaid alcohol or silanol preferably containing 1-20 carbon atoms).Examples of carboxy protecting groups include straight or branched chain(1-12C)alkyl groups (for example isopropyl, and tert-butyl); loweralkoxy-lower alkyl groups (for example methoxymethyl, ethoxymethyl andisobutoxymethyl); lower acyloxy-lower alkyl groups, (for exampleacetoxymethyl, propionyloxymethyl, butyryloxymethyl andpivaloyloxymethyl); lower alkoxycarbonyloxy-lower alkyl groups (forexample 1-methoxycarbonyloxyethyl and 1-ethoxycarbonyloxyethyl);aryl-lower alkyl groups (for example benzyl, 4-methoxybenzyl,2-nitrobenzyl, 4-nitrobenzyl, benzhydryl and phthalidyl); tri(loweralkyl)silyl groups (for example trimethylsilyl andtert-butyldimethylsilyl); tri(lower alkyl)silyl-lower alkyl groups (forexample trimethylsilylethyl); and (2-6C)alkenyl groups (for exampleallyl). Methods particularly appropriate for the removal of carboxylprotecting groups include for example acid-, base-, metal- orenzymically-catalysed hydrolysis.

Examples of hydroxy protecting groups include lower alkyl groups (forexample tert-butyl), lower alkenyl groups (for example allyl); loweralkanoyl groups (for example acetyl); lower alkoxycarbonyl groups (forexample tert-butoxycarbonyl); lower alkenyloxycarbonyl groups (forexample allyloxycarbonyl); aryl-lower alkoxycarbonyl groups (for examplebenzyloxycarbonyl, 4-methoxybenzyloxycarbonyl, 2-nitrobenzyloxycarbonyland 4-nitrobenzyloxycarbonyl); tri(lower alkyl)silyl (for exampletrimethylsilyl and tert-butyldimethylsilyl) and aryl-lower alkyl (forexample benzyl) groups.

Examples of amino protecting groups include formyl, aryl-lower alkylgroups (for example benzyl and substituted benzyl, 4-methoxybenzyl,2-nitrobenzyl and 2,4-dimethoxybenzyl, and triphenylmethyl);di-4-anisylmethyl and furylmethyl groups; lower alkoxycarbonyl (forexample tert-butoxycarbonyl); lower alkenyloxycarbonyl (for exampleallyloxycarbonyl); aryl-lower alkoxycarbonyl groups (for examplebenzyloxycarbonyl, 4-methoxybenzyloxycarbonyl, 2-nitrobenzyloxycarbonyland 4-nitrobenzyloxycarbonyl); trialkylsilyl (for example trimethylsilyland tert-butyldimethylsilyl); alkylidene (for example methylidene) andbenzylidene and substituted benzylidene groups.

Methods appropriate for removal of hydroxy and amino protecting groupsinclude, for example, acid-, base-, metal- or enzymically-catalysedhydrolysis for groups such as 2-nitrobenzyloxycarbonyl, hydrogenationfor groups such as benzyl and photolytically for groups such as2-nitrobenzyloxycarbonyl.

The reader is referred to Advanced Organic Chemistry, 4th Edition, by J.March, published by John Wiley & Sons 1992, for general guidance onreaction conditions and reagents and to Protective Groups in OrganicSynthesis, 2^(nd) Edition, by T. Green et al., also published by JohnWiley & Son, for general guidance on protecting groups.

The quinoline of the Formula II may be prepared by, for example, thereaction of a carboxylic acid of the Formula IV, or a reactivederivative thereof,

wherein Z and R³ have any of the meanings defined hereinbefore exceptthat any functional group is protected if necessary, with an amine ofthe Formula V

wherein R¹ and R² have any of the meanings defined hereinbefore exceptthat any functional group is protected if necessary, whereafter anyprotecting group that is present may be removed by conventional means.

A suitable reactive derivative of a carboxylic acid of the Formula IVis, for example, an acyl halide, for example an acyl chloride formed bythe reaction of the acid and an inorganic acid chloride, for examplethionyl chloride; a mixed anhydride, for example an anhydride formed bythe reaction of the acid and a chloroformate such as isobutylchloroformate; an active ester, for example an ester formed by thereaction of the acid and a phenol such as pentafluorophenol, an esterformed by the reaction of the acid and an ester such aspentafluorophenyl trifluoroacetate or an ester formed by the reaction ofthe acid and an alcohol such as N-hydroxybenzotriazole; an acyl azide,for example an azide formed by the reaction of the acid and an azidesuch as diphenylphosphoryl azide; an acyl cyanide, for example a cyanideformed by the reaction of an acid and a cyanide such asdiethylphosphoryl cyanide; or the product of the reaction of the acidand a carbodiimide such as dicyclohexylcarbodiimide or1-(3-dimethylaminopropyl)-3-ethylcarbodiimide.

The reaction is conveniently carried out in the presence of a suitablebase as defined hereinbefore and in the presence of a suitable inertsolvent or diluent as defined hereinbefore.

Typically a carbodiimide coupling reagent is used in the presence of anorganic solvent (preferably an anhydrous polar aprotic organic solvent)at a non-extreme temperature, for example in the region −10 to 40° C.,typically at ambient temperature of about 20° C.

The quinoline of the Formula IV may be prepared by standard proceduresof organic chemistry such as the relevant procedures illustrated in theaccompanying Examples. For example, a quinolone of the Formula VI

wherein R³ has any of the meanings defined hereinbefore except that anyfunctional group is protected if necessary and wherein the carboxy groupat the 6-position is protected, for example as a lower alkyl (forexample ethyl) ester, may be reacted with a halogenating agentwhereafter the carboxy protecting group at the 6-position is removed byconventional means and any other protecting group that is present may beremoved by conventional means to form a benzoic acid derivative of theFormula IV wherein Z is a halogeno group.

Convenient halogenating agents include, for example, inorganic acidhalides, for example thionyl chloride, phophorus trichloride, phosphorustribromide, phosphoryl chloride and phosphorus pentachloride. Thereaction is conveniently carried out in the presence of an excess of thehalogenating agent as a solvent or diluent or in the presence of aseparate solvent or diluent such as, for example, a halogenated solventsuch as methylene chloride, chloroform or carbon tetrachloride. Thereaction is conveniently carried out at a temperature in the range, forexample, 10 to 150° C., preferably in the range 40 to 100° C.

The quinolone of the Formula VI may be prepared by standard proceduresof organic chemistry such as those relevant procedures illustrated inthe accompanying Examples.

(b) The reaction of a carboxylic acid of the Formula VII, or a reactivederivative thereof as defined hereinbefore,

wherein R³, R⁴ and n have any of the meanings defined hereinbeforeexcept that any functional group is protected if necessary, with anamine of the Formula V

wherein R¹ and R² have any of the meanings defined hereinbefore exceptthat any functional group is protected if necessary, whereafter anyprotecting group that is present is removed by conventional means.

The reaction is conveniently carried out in the presence of a suitablebase as defined hereinbefore and in the presence of a suitable inertsolvent or diluent as defined hereinbefore. Typically a carbodiimidecoupling reagent is used, preferably also in the presence of anester-forming alcohol such as N-hydroxybenzotriazole, and the reactionis carried out at a temperature at or near ambient temperature of about20° C.

The carboxylic acid of the Formula VII may be prepared by, for example,the reaction, conveniently in the presence of a suitable base as definedhereinbefore, of a quinoline of the Formula IV

wherein Z is a displaceable group as defined hereinbefore and R³ has anyof the meanings defined hereinbefore except that any functional group isprotected if necessary and wherein the carboxy group at the 6-positionmay be protected, for example as a lower alkyl (for example ethyl)ester, with a phenol of the Formula III

wherein R⁴ and n have any of the meanings defined hereinbefore exceptthat any functional group is protected if necessary, whereafter anyprotecting group that is present may be removed by conventional means.

The reaction is conveniently carried out in the presence of a suitableinert solvent or diluent or defined hereinbefore and at a temperature inthe range, for example, 10 to 250° C., preferably in the range 50 to150° C.

(c) For the preparation of those compounds of the Formula I wherein R⁴is an amino, (1-6C)alkylamino, di-[(1-6C)alkyl]amino, anilino orN-(1-6C)alkylanilino group, the reaction of a compound of the FormulaVIII wherein R¹, R² and R³ have any of the meanings defined hereinbeforeexcept that any functional group is protected if necessary and Z is adisplaceable group as defined hereinbefore,

with an amine or aniline as appropriate whereafter any protecting groupthat is present is removed by conventional means.

The reaction is conveniently carried out in the presence of a suitablebase as defined hereinbefore and in the presence of a suitable inertsolvent or diluent as defined hereinbefore. Typically the reaction iscarried out at a temperature in the range, for example, 10 to 250° C.,preferably in the range 50 to 100° C.

When, for example, in the compound of the Formula VIII the displaceablegroup Z is a halogeno group, that necessary starting material can beprepared using either of the processes of process variants (a) or (b) asdefined hereinbefore.

When a pharmaceutically-acceptable salt of a quinoline derivative of theFormula I is required, for example an acid-addition salt, it may beobtained by, for example, reaction of said quinoline derivative with asuitable acid using a conventional procedure.

Biological Assays

The following assays can be used to measure the effects of the compoundsof the present invention as p56^(lck) inhibitors, as inhibitors of Tcell activation, as inhibitors of cytokine production in mice and asinhibitors of transplant rejection.

(a) In vitro Enzyme Assay

The ability of test compounds to inhibit phosphorylation by the enzymep56^(lck) of a tyrosine-containing polypeptide substrate was assessedusing a conventional Elisa assay.

The following conventional procedure was used to obtain p56^(lck)enzyme. An EcoR1/Not1 fragment containing the entire coding sequence ofp56^(lck) was generated by the technique of polymerase chain reaction(PCR) from Incyte clone No. 2829606. A 6-His tag was added to thesequence at the N-terminus during the PCR stage. Conventional sequenceanalysis identified a number of changes compared to the publishedsequence and these were found also to have been present in the originalIncyte template. To achieve expression of the enzyme, the PCR fragmentwas inserted downstream of the polyhedrin promotor of pFASTBAC1 (LifeTechnologies Limited, Paisley, UK, Catalogue No. 10360-014). Arecombinant Baculovirus was constructed using the Bac-to-Bac system(Life Technologies Limited). High Five insect cells (Invitrogen BV, POBox 2312, 9704 CH Groningen, The Netherlands, Catalogue No. B855-02)were infected with the recombinant Baculovirus at a multiplicity ofinfection of 1 and incubated for 48 hours. The cells were harvested.Groups of 1.6×10⁹ cells were lysed by incubation in 20 mM Hepes pH7.5buffer containing 10% glycerol, 1% Triton-X-100, magnesium chloride (1.5mM), ethylene glycol bis(β-aminoethyl ether N,N,N′,N′-tetraacetic acid)(EGTA, 1 mM), sodium vanadate (1 mM), sodium fluoride (10 mM), imidazole(5 mM), sodium chloride (150 mM), phenylmethanesulphonyl fluoride (0.1mM), pepstatin (1 μg/ml) and leupeptin (1 μg/ml). A soluble fraction wasobtained by centrifugation and 6-His-p56^(lck) was purified by columnchromatography on a 1 ml Ni-NTA agarose column (Qiagen Limited, Crawley,West Sussex, UK). The protein was eluted using the above-mentionedbuffer except that imidazole (100 mM) was also present. The p56^(lck)enzyme so obtained was stored at −80° C.

Substrate solution [100 μl of a 2 μg/ml solution of the polyamino acidPoly(Glu, Ala, Tyr) 6:3:1 (Sigma Catalogue No. P3899) in phosphatebuffered saline (PBS)] was added to each well of a Nunc 96-wellimmunoplate (Catalogue No. 439454) and the plate was sealed and storedat 4° C. for 16 hours. The excess of substrate solution was discarded,the substrate-coated wells were washed with Hepes pH7.4 buffer(50 mM,300 μl) and blotted dry. Each test compound was dissolved in DMSO anddiluted to give a series of dilutions (from 100 μM to 0.001 μM) of thecompound in a 10:1 mixture of water and DMSO. Portions (25 μl) of eachdilution of test compound were transferred to the 96-well assay plate.Aliquots (25 μl) of a 10:1 mixture of water and DMSO were added followedby aliquots (25 μl ) of a mixture of adenosine triphosphate (ATP; 24 μlof a 1 mM aqueous solution) and manganese chloride (3 ml of a 40 mMaqueous solution).

p56^(lck) enzyme (0.3μl of a 0.5 mg/ml stock solution) was diluted in amixture of Hepes pH 7.4 buffer (200 mM, 3 ml), sodium orthovanadate (2mM, 0.6 ml), 1% Triton X-100 (0.6 ml), dithiothreitol (25 mM, 48 μl) anddistilled water (1.8 ml). Aliquots (50 μl) of the resultant solutionwere transferred to each well in the assay plate and the plate wasincubated at ambient temperature for 8 minutes. The wells were washedsequentially with two aliquots (300 μl) of phosphate-buffered saline(PBS) containing 0.1% Tween 20 (hereinafter PBS/T).

Aliquots (100 μl) were added to each well of a mixture ofantiphosphotyrosine-4G10 monoclonal IgG2 bk antibody (UBI Catalogue No.05-321; 30 μl of a 50 μg/ml solution of the antibody in PBS/T), PBS/T(11 ml) and bovine serum albumin (BSA; Sigma Catalogue No. A6793; 55 mg)and the plate was incubated at ambient temperature for 1 hour. The wellswere washed sequentially with two aliquots (300 μl) of PBS/T and blotteddry. Aliquots (100 μl) were added to each well of a mixture of sheepanti-mouse IgG-peroxidase antibody (Amersham Catalogue No. NXA931; 20μl), PBS/T (11 ml) and BSA (55 mg) and the plate was incubated atambient temperature for 1 hour. The wells were washed sequentially withtwo aliquots (300 μl) of PBS/T and blotted dry.

Aliquots (100 μl) were added to each well of an ABTS solution [preparedby adding an 2,2′-azinobis(3-ethylbenzothiazolinesulphonic acid) (ABTS)tablet (50 mg; Boehringer Catalogue No, 1204521) to a mixture (50 mM) ofphosphate-citrate pH5.0 buffer and 0.03% sodium perborate (obtained byadding a PCSB capsule (Sigma Catalogue No. P-4922) to distilled water(100 ml))]. The plate was incubated at ambient temperature for 1.5 hoursand the absorbance at 405 nm was determined.

The extent of inhibition of the phosphorylation reaction at a range ofconcentrations of each test compound was determined and an IC₅₀ valuewas calculated.

(b) In vitro T Cell Proliferation Assays

The ability of test compounds to inhibit T cell proliferation wasassessed by using human peripheral blood mononuclear cells andstimulation of the T cells by way of the T cell receptor or other thanby way of the T cell receptor.

Peripheral blood mononuclear cells (PBMC) were isolated from heparinised(10 units/ml heparin) human blood by density centrifugation(Lymphoprep™; Nycomed) spinning initially at 2000 rpm at ambienttemperature for 20 minutes. Cells at the interphase were transferred toclean tubes, diluted 1:1 with RPMI 1640 medium (Gibco) and spun at 2000rpm at ambient temperature for 10 minutes. The cell pellet wasresuspended in RPMI 1640 medium and spun at 1400 rpm at ambienttemperature for 10 minutes. The cell pellet was resuspended in RPMI 1640medium and spun at 900 rpm at ambient temperature for 10 minutes toremove platelets. The prepared mononuclear cells were resuspended in anassay medium comprising RPMI 1640 culture medium supplemented with 50units/ml penicillin, 50 μg/ml streptomycin, 1 mM glutamine and 10%heat-inactivated human AB serum.

Test compounds were solubilised in DMSO at a concentration of 10 mM anddiluted 1:83.3 in assay medium. Aliquots (75 μl) were added to each wellof a 96 well flat-bottomed tissue culture plate and subsequently serial1 to 3 dilutions were made into assay medium giving final testconcentrations in the range 0.1 to 30 μM. Control wells contained assaymedium (50 μl) containing 1.2% DMSO. PBMCs (100 μl of a suspension of2×10⁶ cells/ml in assay medium) were added to each well and incubatedfor 1 hour at 37° C. in a humidified (5%CO₂/95% air) incubator.

The extent of inhibition of T cell proliferation at a range ofconcentrations of each test compound was determined and an IC₅₀ valuewas calculated.

(b)(i) T Cell Receptor Stimulation

Aliquots (50 μl) of the T cell receptor stimulatory anti-CD3 antibody(Pharmingen Catalogue No. 30100D; 40 ng/ml in assay medium) were addedto each well and the cells were incubated for 24 hours at 37° C. in ahumidified (5%CO₂/95% air) incubator. Tritiated thymidine (1 μCi perwell) was added and the cells were incubated for up to a further 24hours at 37° C. The cells were harvested onto a filter mat andradioactivity was counted using a Wallac 1450 Microbeta Plus liquidscintillation counter.

(b)(ii) Non T Cell Receptor Stimulation

Aliquots (50 μl) of a mixture of the cell stimulants PMA(phorbol-12-myristate-13-acetate, Sigma Catalogue No. P8139; 40 ng/ml)and Ionomycin (Sigma Catalogue No. I0684; 1.2 μM) were added to eachwell and the cells were incubated and analysed as described in paragraph(b)(i).

(c) In vivo Skin Graft Rejection Test

The ability of test compounds to inhibit rodent skin allograft rejectionwas assessed using analogous procedures to those disclosed by J. Magaeet al., Cellular Immunology, 1996, 173, 276-281 and R. Tsuji et al., J.Antibiot., 1992, 45, 1295 to assess the effect of cyclosporin A on Tcell properties in vivo.

(d) Test as Anti-arthritic Agent

Activity of a test compound as an anti-arthritic agent was assessed asfollows. Acid soluble native type II collagen has been shown to bearthritogenic in rats causing polyarthritis when administered in Freundsincomplete adjuvant by (D. E. Trentham et al. J. Exp. Med., 1977, 146,857). This is now known as collagen-induced arthritis (CIA) and similarconditions can be induced in mice and primates. CIA in DBA/1 mice asdescribed by R. O. Williams et al., Proc Natl. Acad Sci., 1992, 89, 9784and Immunology, 1995, 84, 433 is a tertiary model which can be used todemonstrate the anti-arthritic activity of a test compound.

Although the pharmacological properties of the compounds of the FormulaI vary with structural change as expected, in general activity possessedby compounds of the Formula I may be demonstrated at the followingconcentrations or doses in one or more of the above tests (a), (b), (c)and (d):

Test (a):—IC₅₀ in the range, for example, 0.001-10 μM;

Test (b)(i):—IC₅₀ in the range, for example, 0.1-20 μM;

Test (b)(ii):—IC₅₀ in the range, for example, 5->30 μM;

Test (c):—activity in the range, for example, 1-100 mg/kg;

Test (d):—activity in the range, for example, 1-100 mg/kg;.

No physiologically-unacceptable toxicity was observed at the effectivedose for compounds tested of the present invention.

By way of example,4-(4-chloro-2-fluorophenoxy)-7-methoxy-N-(3-morpholinopropyl)quinoline-6-carboxamide(Example 1) has an IC₅₀ of approximately 0.03 μM in Test (a); an IC₅₀ ofapproximately 0.7 μM in Test (b)(i) and an IC₅₀ of approximately 18 μMin Test (b)(ii).

According to a further aspect of the invention there is provided apharmaceutical composition which comprises a quinoline derivative of theFormula I, or a pharmaceutically-acceptable salt thereof, as definedhereinbefore in association with a pharmaceutically-acceptable diluentor carrier.

The compositions of the invention may be in a form suitable for oral use(for example as tablets, lozenges, hard or soft capsules, aqueous oroily suspensions, emulsions, dispersible powders or granules, syrups orelixirs), for topical use (for example as creams, ointments, gels, oraqueous or oily solutions or suspensions), for administration byinhalation (for example as a finely divided powder or a liquid aerosol),for administration by insufflation (for example as a finely dividedpowder) or for parenteral administration (for example as a sterileaqueous or oily solution for intravenous, subcutaneous, intramuscular orintramuscular dosing or as a suppository for rectal dosing).

The compositions of the invention may be obtained by conventionalprocedures using conventional pharmaceutical excipients, well known inthe art. Thus, compositions intended for oral use may contain, forexample, one or more colouring, sweetening, flavouring and/orpreservative agents.

The amount of active ingredient that is combined with one or moreexcipients to produce a single dosage form will necessarily varydepending upon the host treated and the particular route ofadministration. For example, a formulation intended for oraladministration to humans will generally contain, for example, from 0.5mg to 0.5 g of active agent compounded with an appropriate andconvenient amount of excipients which may vary from about 5 to about 98percent by weight of the total composition.

The size of the dose for therapeutic or prophylactic purposes of acompound of the Formula I will naturally vary according to the natureand severity of the conditions, the age and sex of the animal or patientand the route of administration, according to well known principles ofmedicine.

In using a compound of the Formula I for therapeutic or prophylacticpurposes it will generally be administered so that a daily dose in therange, for example, 0.5 mg/kg to 75 mg/kg body weight is received, givenif required in divided doses. In general lower doses will beadministered when a parenteral route is employed. Thus, for example, forintravenous administration, a dose in the range, for example, 0.5 mg/kgto 30 mg/kg body weight will generally be used. Similarly, foradministration by inhalation, a dose in the range, for example, 0.5mg/kg to 25 mg/kg body weight will be used. Oral administration ishowever preferred, particularly in tablet form. Typically, unit dosageforms will contain about 0.5 mg to 0.5 g of a compound of thisinvention.

According to a further aspect of the invention there is provided aquinoline derivative of the Formula I, or a pharmaceutically-acceptablesalt thereof, as defined hereinbefore for use in a method of treatmentof the human or animal body by therapy.

We have found that the compounds of the present invention are of use inthe prevention or treatment of autoimmune diseases or medicalconditions, for example T cell mediated disease such as transplantrejection, rheumatoid arthritis or multiple sclerosis. We have furtherfound that these effects are believed to arise by virtue of inhibitionof one or more of the multiple tyrosine-specific protein kinases whichare involved in the early signal transduction steps which lead to full Tcell activation, for example by way of inhibition of the enzymep56^(lck). Accordingly the compounds of the present invention areexpected to be useful in the prevention or treatment of T cell mediateddiseases or medical conditions. In particular the compounds of thepresent invention are expected to be useful in the prevention ortreatment of those pathological conditions which are sensitive toinhibition of one or more of the multiple tyrosine-specific proteinkinases which are involved in the early signal transduction steps whichlead to T cell activation, for example by way of inhibition of p56^(lck)tyrosine kinase. Further, the compounds of the present invention areexpected to be useful in the prevention or treatment of those diseasesor medical conditions which are mediated alone or in part by inhibitionof the enzyme p56^(lck), i.e. the compounds may be used to produce ap56^(lck) enzyme inhibitory effect in a warm-blooded animal in need ofsuch treatment. Specifically, the compounds of the present invention areexpected to be useful in the prevention or treatment of autoimmuneconditions or diseases such as inflammatory diseases (for examplerheumatoid arthritis, inflammatory bowel disease, glomerulonephritis andlung fibrosis), multiple sclerosis, psoriasis, hypersensitivityreactions of the skin, atherosclerosis, restenosis, allergic asthma andinsulin-dependent diabetes. In particular the compounds of the presentinvention are expected to be useful in the prevention or treatment ofthe acute rejection of transplanted tissue or organs.

Thus according to this aspect of the invention there is provided the useof a quinoline derivative of the Formula I, or apharmaceutically-acceptable salt thereof, as defined hereinbefore in themanufacture of a medicament for use in the prevention or treatment of Tcell mediated diseases or medical conditions in a warm-blooded animalsuch as man.

According to a further feature of this aspect of the invention there isprovided a method for the prevention or treatment of T cell mediateddiseases or medical conditions in a warm-blooded animal, such as man, inneed of such treatment which comprises administering to said animal aneffective amount of a quinoline derivative of the Formula I, or apharmaceutically-acceptable salt thereof, as defined hereinbefore.

According to a further feature of the invention there is provided theuse of a quinoline derivative of the Formula I, or apharmaceutically-acceptable salt thereof, as defined hereinbefore in themanufacture of a medicament for use in the prevention or treatment ofthose pathological conditions which are sensitive to inhibition of oneor more of the multiple tyrosine-specific protein kinases which areinvolved in the early signal transduction steps which lead to T cellactivation.

According to a further feature of the invention there is provided amethod for the prevention or treatment of those pathological conditionswhich are sensitive to inhibition of one or more of the multipletyrosine-specific protein kinases which are involved in the early signaltransduction steps which lead to T cell activation which comprisesadministering to said animal an effective amount of a quinolinederivative of the Formula I, or a pharmaceutically-acceptable saltthereof, as defined hereinbefore.

As stated above the size of the dose required for the therapeutic orprophylactic treatment of T cell mediated disease will necessarily bevaried depending on the host treated, the route of administration andthe severity of the illness being treated. A unit dose in the range, forexample, 0.5 mg/kg to 75 mg/kg body weight, preferably 0.5 mg/kg to 30mg/kg body weight, is envisaged, given if required in divided doses.

We have also found that at higher doses the compounds of the presentinvention possess anti-proliferative properties which are believed toarise from their Class I (EGF type) receptor tyrosine kinase inhibitoryactivity. Accordingly the compounds of the present invention areexpected to be useful in the treatment of diseases or medical conditionsmediated alone or in part by Class I receptor tyrosine kinase enzymes,i.e. the compounds may be used to produce a Class I receptor tyrosinekinase inhibitory effect in a warm-blooded animal in need of suchtreatment. Thus the compounds of the present invention provide a methodfor treating the proliferation of malignant cells characterised byinhibition of Class I receptor tyrosine kinase enzymes, i.e. thecompounds may be used to produce an anti-proliferative effect mediatedalone or in part by the inhibition of Class I receptor tyrosine kinase.Accordingly the compounds of the present invention are expected to beuseful in the treatment of cancer by providing an anti-proliferativeeffect, particularly in the treatment of Class I receptor tyrosinekinase sensitive cancers such as cancers of the breast, lung, colon,rectum, stomach, prostate, bladder, pancreas and ovary. The compounds ofthe present invention are also expected to be useful in the treatment ofother cell-proliferation diseases such as psoriasis, benign prostatichypertrophy, atherosclerosis and restenosis.

According to this aspect of the invention there is provided the use of aquinoline derivative of the formula I, or a pharmaceutically-acceptablesalt thereof, as defined hereinbefore in the manufacture of a medicamentfor use in the production of an anti-proliferative effect in awarm-blooded animal such as man.

According to a further feature of this aspect of the invention there isprovided a method for producing an anti-proliferative effect in awarm-blooded animal, such as man, in need of such treatment whichcomprises administering to said animal an effective amount of aquinoline derivative of the formula I, or a pharmaceutically-acceptablesalt thereof, as defined hereinbefore.

The size of the dose required to produce an anti-proliferative effect ina warm-blooded animal such as man will necessarily be varied dependingon the host treated, the route of administration and the severity of theillness being treated. A unit dose in the range, for example, 5 mg/kg to150 mg/kg body weight, preferably 5 mg/kg to 100 mg/kg body weight, isenvisaged, given if required in divided doses.

The compounds of this invention may be used in combination with otherdrugs and therapies used in the treatment of T cell mediated disease.For example, the compounds of the Formula I could be used in combinationwith drugs and therapies used in the treatment of autoimmune conditionsor diseases such as inflammatory diseases (for example rheumatoidarthritis, inflammatory bowel disease, glomerulonephritis and lungfibrosis), multiple sclerosis, psoriasis, hypersensitivity reactions ofthe skin, atherosclerosis, restenosis, allergic asthma andinsulin-dependent diabetes. In particular the compounds of the Formula Icould be used in combination with drugs and therapies such ascyclosporin A used in the prevention or treatment of the acute rejectionof transplanted organs.

For example, the compounds of the Formula I are of value in thetreatment of certain inflammatory and non-inflammatory diseases whichare currently treated with a cyclooxygenase-inhibitory non-steroidalanti-inflammatory drug (NSAID) such as indomethacin, ketorolac,acetylsalicyclic acid, ibuprofen, sulindac, tolmetin and piroxicam.Co-administration of a compound of the Formula I with a NSAID can resultin a reduction of the quantity of the latter agent needed to produce atherapeutic effect. Thereby the likelihood of adverse side-effects fromthe NSAID such as gastrointestinal effects are reduced. Thus accordingto a further feature of the invention there is provided a pharmaceuticalcomposition which comprises a compound of the Formula I, or apharmaceutically-acceptable salt thereof, in conjunction or admixturewith a cyclooxygenase inhibitory non-steroidal anti-inflammatory agent,and a pharmaceutically-acceptable diluent or carrier.

The compounds of the invention may also be used with anti-inflammatoryagents such as an inhibitor of the enzyme 5-lipoxygenase. The compoundsof the invention may also be used with anti-inflammatory agents such asan inhibitor of the enzyme COX-2 such as celecoxib or rofecoxib.

The compounds of the Formula I may also be used in the treatment ofconditions such as rheumatoid arthritis in combination withantiarthritic agents such as gold, methotrexate, steroids andpenicillinamine, and in conditions such as osteoarthritis in combinationwith steroids.

The compounds of the present invention may also be administered indegradative diseases, for example osteoarthritis, withchondroprotective, anti-degradative and/or reparative agents such asDiacerhein, hyaluronic acid formulations such as Hyalan, Rumalon,Arteparon and glucosamine salts such as Antril.

The compounds of the Formula I may be be used in the treatment of asthmain combination with antiasthmatic agents such as bronchodilators andleukotriene antagonists.

The anti-proliferative treatment defined hereinbefore may be applied asa sole therapy or may involve, in addition to the quinoline derivativeof the invention, conventional radiotherapy or one or more otheranti-tumour substances, for example cytotoxic or cytostatic anti-tumoursubstances, for example those selected from, for example, mitoticinhibitors, for example vinblastine, vindesine and vinorelbine;alkylating agents, for example cis-platin, carboplatin andcyclophosphamide; antimetabolites, for example 5-fluorouracil, tegafur,methotrexate, cytosine arabinoside and hydroxyurea, or, for example, oneof the preferred antimetabolites disclosed in European PatentApplication No. 239362 such asN-{5-[N-(3,4-dihydro-2-methyl-4-oxoquinazolin-6-ylmethyl)-N-methylamino]-2-thenoyl)}-L-glutamicacid; intercalating antibiotics, for example adriamycin, mitomycin andbleomycin; enzymes, for example asparaginase; topoisomerase inhibitors,for example etoposide and camptothecin; biological response modifiers,for example interferon; and anti-hormones, for example antioestrogenssuch as tamoxifen, for example antiandrogens such as4′-cyano-3-(4-fluorophenylsulphonyl)-2-hydroxy-2-methyl-3′-(trifluoromethyl)propionanilideor, for example LHRH antagonists or LHRH agonists such as goserelin,leuprorelin or buserelin and hormone synthesis inhibitors, for examplearomatase inhibitors such as those disclosed in European PatentApplication No. 0296749, for example2,2′-[5-(1H-1,2,4-triazol-1-ylmethyl)-1,3-phenylene]bis(2-methylpropionitrile),and, for example, inhibitors of 5α-reductase such as17β-(N-tert-butylcarbamoyl)-4-aza-5α-androst-1-en-3-one. Such conjointtreatment may be achieved by way of the simultaneous, sequential orseparate dosing of the individual components of the treatment. Accordingto this aspect of the invention there is provided a pharmaceuticalproduct comprising a quinoline derivative of the formula I as definedhereinbefore and an additional anti-tumour substance as definedhereinbefore for the conjoint treatment of cancer.

If formulated as a fixed dose such combination products employ thecompounds of this invention within the dosage range described herein andthe other pharmaceutically-active agent within its approved dosagerange. Sequential use is contemplated when a combination formulation isinappropriate.

Although the compounds of the Formula I are primarily of value astherapeutic agents for use in warm-blooded animals (including man), theyare also useful whenever it is required to inhibit the effects of T cellactivation. Thus, they are useful as pharmacological standards for usein the development of new biological tests and in the search for newpharmacological agents.

The invention will now be illustrated in the following non-limitingExamples in which, unless otherwise stated:

(i) operations were carried out at ambient temperature, i.e. in therange 17 to 25° C. and under an atmosphere of an inert gas such as argonunless otherwise stated;

(ii) evaporations were carried out by rotary evaporation in vacuo andwork-up procedures were carried out after removal of residual solids byfiltration;

(iii) column chromatography (by the flash procedure) and medium pressureliquid chromatography (MPLC) were performed on Merck Kieselgel silica(Art. 9385) or Merck Lichroprep RP-18 (Art. 9303) reversed-phase silicaobtained from E. Merck, Darmstadt, Germany or high pressure liquidchromatography (HPLC) was performed on C18 reverse phase silica, forexample on a Dynamax C-18 60 Å preparative reversed-phase column;

(iv) yields, where present, are given for illustration only and are notnecessarily the maximum attainable;

(v) in general, the end-products of the Formula I have satisfactorymicroanalyses and their structures were confirmed by nuclear magneticresonance (NMR) and/or mass spectral techniques; fast-atom bombardment(FAB) mass spectral data were obtained using a Platform spectrometerand, where appropriate, either positive ion data or negative ion datawere collected; NMR chemical shift values were measured on the deltascale [proton magnetic resonance spectra were determined using a VarianGemini 2000 spectrometer operating at a field strength of 300 MHz or aBruker AM250 spectrometer operating at a field strength of 250 MHz]; thefollowing abbreviations have been used: s, singlet; d, doublet; q,quartet; t, triplet; m, multiplet; br, broad;

(vi) intermediates were not generally fully characterised and purity wasassessed by thin layer chromatographic, HPLC, infra-red (IR) and/or NMRanalysis;

(vii) melting points are uncorrected and were determined using a MettlerSP62 automatic melting point apparatus or an oil-bath apparatus; meltingpoints for the end-products of the Formula I were determined aftercrystallisation from a conventional organic solvent such as ethanol,methanol, acetone, ether or hexane, alone or in admixture; and

(viii) the following abbreviations have been used:

DMF N,N-dimethylformamide

DMSO dimethylsulphoxide

THF tetrahydrofuran

EXAMPLE 14-(4-chloro-2-fluorophenoxy)-7-methoxy-N-(3-morpholinopropyl)quinoline-6-carboxamide

N-Hydroxybenzotriazole (0.104 g), triethylamine (0.095 ml),N-(3-aminopropyl)morpholine (0.11 ml) and1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.142 g)were added in turn to a stirred mixture of4-(4-chloro-2-fluorophenoxy)-7-methoxyquinoline-6-carboxylic acid (0.2g) in DMF (5 ml). The reaction mixture was stirred at ambienttemperature for 16 hours. Water (20 ml) was added and the resultantsuspension was transferred onto a C18 reversed-phase silica gelchromatography column and eluted with a decreasingly polar solventgradient of water and acetonitrile. There was thus obtained the titlecompound (0.175 g); NMR Spectrum: (DMSOd₆) 1.72 (m, 2H), 2.38 (m, 6H),3.35 (m, 2H), 3.56 (m, 4H), 4.01 (s, 3H), 6.56 (d, 1H), 7.42-7.59 (m,3H), 7.76 (m, 1H), 8.38 (m, 1H), 8.51 (s, 1H), 8.68 (d, 1H); MassSpectrum: M+H⁺ 474 & 476.

The 4-(4-chloro-2-fluorophenoxy)-7-methoxyquinoline-6-carboxylic acidused as a starting material was prepared as follows:

A suspension of methyl 4-amino-2-methoxybenzoate (26.5 g) in isopropanol(500 ml) was stirred and heated to 50° C. for 10 minutes.2,2-Dimethyl-5-methoxymethylene-1,3-dioxane-4,6-dione (methoxymethyleneMeldrum's Acid, 25.6 g) was added and the resultant suspension waswarmed to 80° C. and stirred for 40 minutes. The reaction mixture wasallowed cool to ambient temperature and the white precipitate wasisolated and washed with diethyl ether. There was thus obtained2,2-dimethyl-5-(3-methoxy-4-methoxycarbonyl-anilinomethylene)-1,3-dioxane-4,6-dione(40.5 g); NMR Spectrum: (CDCl₃) 1.77 (s, 6H), 3.88 (s, 3H), 3.96 (s,3H), 6.75 (s, 1H), 6.87 (d, 1H), 7.92 (d, 1H), 8.67 (d, 1H), 11.29 (d,1H); Mass Spectrum: M+H⁺ 279.

A suspension of a portion (25 g) of the material so obtained in amixture of diphenyl ether (225 ml) and biphenyl (75 ml) was stirred andheated to 240° C. for 1 hour. The solution was allowed to cool toambient temperature. The resultant precipitate was isolated and washedwith diethyl ether. There was thus obtained methyl7-methoxy-4-oxo-1,4-dihydroquinoline-6-carboxylate (14 g); NMR Spectrum:(DMSOd₆) 3.81 (s, 3H), 3.89 (s, 3H), 5.99 (d, 1H), 7.01 (s, 1H), 7.85(m, 1H), 8.42 (s, 1H), 11.71 (broad s, 1H); Mass Spectrum: M+H⁺ 234.

A mixture of a portion (3.9 g) of the material so obtained, thionylchloride (50 ml) and DMF (a few drops) and stirred and heated to refluxfor 2 hours. The resultant mixture was evaporated and the residue wasazeotroped with toluene (2×100 ml). The residue was partitioned betweenmethylene chloride and a dilute aqueous sodium bicarbonate solution. Theorganic phase was washed with a saturated aqueous sodium bicarbonatesolution, dried over magnesium sulphate and evaporated. The residue wastriturated under a 1:1 mixture of isohexane and diethyl ether and theresultant precipitate was isolated and washed with isohexane. There wasthus obtained methyl 4-chloro-7-methoxyquinoline-6-carboxylate (3.7 g);NMR Spectrum: (CDCl₃) 3.99 (s, 3H), 4.04 (s, 3H), 7.38 (d, 1H), 7.52 (s,1H), 8.62 (s, 1H), 8.75 (d, 1H); Mass Spectrum: M+H⁺ 252 & 254.

A mixture of the material so obtained, 4-chloro-2-fluorophenol (4.05 g),potassium carbonate (7 g) and DMF (100 ml) was stirred and heated to100° C. for 7 hours. A second portion (7 g) of potassium carbonate wasadded and the mixture heated to 100° C. for a further 16 hours. Themixture was allowed to cool to ambient temperature and was partitionedbetween ethyl acetate and water. The aqueous phase was re-extracted withethyl acetate and the combined organic phases were washed with asaturated aqueous sodium chloride solution, dried over magnesiumsulphate and evaporated. The residue was triturated under isohexane andthe resultant precipitate was isolated and washed with isohexane. Therewas thus obtained methyl4-(4-chloro-2-fluorophenoxy)-7-methoxyquinoline-6-carboxylate (3.8 g);NMR Spectrum: (CDCl₃) 3.98 (s, 3H), 4.05 (s, 3H), 6.39 (m, 1H),7.19-7.35 (m, 3H), 7.51 (s, 1H), 8.67 (d, 1H), 8.81 (s, 1H); MassSpectrum: M+H⁺ 362 & 364.

A mixture of a portion (3.35 g) of the material so obtained, lithiumhydroxide monohydrate (2.4 g), THF (70 ml), water (35 ml) and methanol(35 ml) was stirred at ambient temperature for 3 hours. The mixture wasevaporated and the residue was partitioned between ethyl acetate andwater. The aqueous phase was re-extracted with ethyl acetate. Theaqueous phase was acidified to pH4 by the dropwise addition of 2Naqueous hydrochloric acid. The resultant precipitate was isolated anddried. Thus was obtained4-(4-chloro-2-fluorophenoxy)-7-methoxyquinoline-6-carboxylic acid (2.1g). NMR Spectrum: (DMSOd₆) 3.97 (s, 3H), 6.59 (d, 1H), 7.41-7.61 (m,3H), 7.76 (m, 1H) 8.54 (s, 1H), 8.7 (d, 1H); Mass Spectrum: M+H⁺ 348 &350.

EXAMPLE 2

Using an analogous procedure to that described in Example 1, theappropriate 4-phenoxyquinoline-6-carboxylic acid was reacted with theappropriate amine to give the compounds described in Table I.

TABLE I

No. (R⁴)_(n) R¹ R² Note  1 4-chloro-2-fluoro2-(2-oxoimidazolidin-1-yl)ethyl H (a)  2 4-chloro-2-fluoro2-(4-aminophenyl)ethyl H (b)  3 4-chloro-2-fluoro 3-phenylpropyl H (c) 4 4-chloro-2-fluoro 2-(2-pyridyl)ethyl H (d)  5 4-chloro-2-fluoro2-morpholinoethyl H (e)  6 4-chloro-2-fluoro2-(2,4-dioxo-5-methylthiazolidin- H (f) 3-yl)ethyl  7 4-chloro-2-fluoro2-(2,4-dioxoimidazolidin-1-yl)ethyl H (g)  8 4-chloro-2-fluoro2-(2-oxopyrrolidin-1-yl)ethyl H (h)  9 4-chloro-2-fluoro3-(2-oxopyrrolidin-1-yl)propyl H (i) 10 4-chloro-2-fluoro3-(4-methylpiperazin-1-yl)propyl H (j) 11 4-chloro-2-fluoro3-(2,6-dioxopiperidin-1-yl)propyl H (k) 12 4-chloro-2-fluoro2-methoxyethyl H (l) 13 4-chloro-2-fluoro 3-methoxypropyl H (m) 144-chloro-2-fluoro 2-methylthioethyl H (n) 15 4-chloro-2-fluoro3-methylthiopropyl H (o) 16 4-chloro-2-fluoro 2-methylsulphonylethyl H(p) 17 4-chloro-2-fluoro 2-(N-propylsulphamoyl)ethyl H (q) 184-chloro-2-fluoro 3-(1-imidazolyl)propyl H (r) 19 4-chloro-2-fluoro4-(1-imidazolyl)butyl H (s) 20 4-chloro-2-fluoro 5-(1-imidazolyl)pentylH (t) 21 4-chloro-2-fluoro 2-(1-imidazolyl)ethyl H (u) 224-chloro-2-fluoro 2-(4-imidazolyl)ethyl H (v) 23 4-chloro-2-fluoro2-(2-thienyl)ethyl H (w)

Notes

(a) The product gave the following data: NMR Spectrum: (CDCl₃) 3.42-3.63(m, 6H), 3.72 (m, 2H), 4.12 (s, 3H), 4.38 (s, 1H), 6.41 (d, 1H),7.14-7.32 (m, 3H), 7.52 (s, 1H), 8.19 (m, 1H), 8.64 (d, 1H), 9.21 (s,1H); Mass Spectrum: M+H⁺ 459 & 461.

(b) The product gave the following data: NMR Spectrum: (CDCl₃) 2.86 (t,2H), 3.77 (m, 2H), 3.94 (s, 3H), 6.39 (d, 1H), 6.71 (d, 2H), 7.08 (d,2H), 7.19-7.33 (m, 3H), 7.5 (s, 1H), 7.91 (t, 1H), 8.66 (d, 1H), 9.23(s, 1H); Mass Spectrum: M+H⁺ 466 & 468.

(c) The product gave the following data: NMR Spectrum: (CDCl₃) 2.01 (m,2H), 2.76 (t, 2H), 3.57 (m, 2H), 4.11 (s, 3H), 6.4 (m, 1H), 7.13-7.34(m, 8H), 7.56 (s, 1H), 7.88 (t, 1H), 8.66 (d, 1H), 9.25 (s, 1H); MassSpectrum: M+H⁺ 465 & 467.

(d) The product gave the following data: NMR Spectrum (CDCl₃) 3.16 (t,2H), 3.97 (q, 2H), 4.0 (s, 3H), 6.39 (d, 1H), 7.15-7.33 (m, 5H), 7.48(s, 1H), 7.64 (m, 1H), 8.43 (m, 1H), 8.6 (m, 1H), 8.62 (d, 1H), 9.23 (s,1H); Mass Spectrum: M+H⁺ 452 & 454.

(e) The product gave the following data: NMR Spectrum: (CDCl₃) 2.55 (m,6H), 3.64 (m, 2H), 3.78 (m, 4H), 4.12 (s, 3H), 6.39 (d, 1H), 7.11-7.32(m, 3H), 7.51 (s, 1H), 8.39 (m, 1H), 8.64 (d, 1H), 9.26 (s, 1H); MassSpectrum: M+H⁺ 460 & 462.

(f) The product gave the following data: Mass Spectrum: M+H⁺ 504 & 506.

(g) The product gave the following data: Mass Spectrum: M+H⁺ 473 & 475.

(h) The product gave the following data: Mass Spectrum: M+H⁺ 458 & 460.The 2-(2-oxopyrrolidin-1-yl)ethylamine, used as a starting material, wasobtained as described in Chem. Express, 1993, 8, 825-828.

(i) The product gave the following data: Mass Spectrum: M+H⁺ 472 & 474.

(j) The product gave the following data: Mass Spectrum: M+H⁺ 487 & 489.

(k) The product gave the following data: Mass Spectrum: M+H⁺ 500 & 502.The 3-(2,6,dioxopiperidin-1-yl)propylamine, used as a starting material,was obtained using an analogous procedure to that described in J. Amer.Chem. Soc., 1965, 87, 2003.

(l) The product gave the following data: Mass Spectrum: M+H⁺ 405 & 407.

(m) The product gave the following data: Mass Spectrum: M+H⁺ 419 & 421.

(n) The product gave the following data: Mass Spectrum: M+H⁺ 421 & 423.

(o) The product gave the following data: Mass Spectrum: M+H⁺ 435 & 437.

(p) The product gave the following data: Mass Spectrum: M+H⁺ 453 & 455.The 2-methylsulphonylethylamine, used as a starting material, wasobtained as described in Biochem. Pharmacol., 1989, 38, 399-406.

(q) The product gave the following data: Mass Spectrum: M+H⁺ 496 & 498.

(r) The product gave the following data: Mass Spectrum: M+H⁺ 455 & 457.

(s) The product gave the following data: Mass Spectrum: M+H⁺ 469 & 471.The 4-(1-imidazolyl)butylamine, used as a starting material, wasobtained as described in J. Med. Chem., 1986, 29, 523-530.

(t) The product gave the following data: Mass Spectrum: M+H⁺ 483 & 485.The 5-(1-imidazolyl)pentylamine, used as a starting material, wasobtained as described in J. Med. Chem., 1986, 29, 523-530.

(u) The product gave the following data: Mass Spectrum: M+H⁺ 441 & 443.The 2-(1-imidazolyl)ethylamine, used as a starting material, wasobtained as described in Synth. Commun., 1991, 21, 535.

(v) The product gave the following data: Mass Spectrum: M+H⁺ 441 & 443.

(w) The product gave the following data: Mass Spectrum: M+H⁺ 457 & 459.

EXAMPLE 3N-[2-(4-chlorophenyl)ethyl]4-(4-chloro-2-fluorophenoxy)-7-methoxyquinoline-6-carboxamide

Triethylamine (0.075 ml), N-hydroxybenzotriazole (0.075 g),2-(4-chlorophenyl)ethylamine (0.092 g) and1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.137 g)were added in turn to a stirred mixture of4-(4-chloro-2-fluorophenoxy)-7-methoxyquinoline-6-carboxylic acid (0.2g) in acetonitrile (5 ml). The reaction mixture was stirred at ambienttemperature for 16 hours. The mixture was evaporated and the residue waspartitioned between chloroform and water. The organic phase was driedover magnesium sulphate and evaporated. The residue was trituratedsequentially under diethyl ether and isohexane. The resultantprecipitate was isolated. There was thus obtained the title compound(0.061 g); NMR Spectrum: (CDCl₃): 2.97 (t, 2H), 3.81 (m, 2H), 3.97 (s,3H), 6.4 (d, 1H), 7.16-7.35 (m, 7H), 7.48 (s, 1H), 7.85 (m, 1H), 8.65(d, 1H), 9.25 (s, 1H); Mass Spectrum: M+H⁺ 486 & 488.

EXAMPLE 4

Using an analogous procedure to that described in Example 3, theappropriate 4-phenoxyquinoline-6-carboxylic acid was reacted with theappropriate amine to give the compound described in Table II.

TABLE II

No. (R⁴)_(n) R¹ R² Note 1 4-chloro-2-fluoro 2-(4-methoxyphenyl)ethyl H(a)

Note

(a) The product gave the following data: NMR Spectrum: (CDCl₃) 2.92 (t,2H), 3.79 (m, 2H), 3.81 (s, 3H), 3.92 (s, 3H), 6.38 (d, 1H), 6.9 (d,2H), 7.13-7.33 (m, 5H), 7.49 (s, 1H), 7.88 (t, 1H), 8.63 (d, 1H), 9.26(s, 1H); Mass Spectrum: M+H⁺ 481 & 483.

EXAMPLE 57-methoxy-N-(3-morpholinopropyl)-4-(4-phenoxyphenoxy)quinoline-6-carboxamide

A mixture of4-chloro-7-methoxy-N-(3-morpholinopropyl)quinoline-6-carboxamide (0.154g), 4-phenoxyphenol (0.11 g), potassium carbonate (0.207 g) and DMF (4ml) was stirred and heated to 100° C. for 16 hours. The mixture wasevaporated and the residue was partitioned between ethyl acetate andwater. The aqueous phase was further extracted with ethyl acetate andthe combined organic extracts were washed with a saturated aqueoussodium chloride solution, dried over magnesium sulphate and evaporated.The residue was purified by column chromatography on silica usingincreasingly polar mixtures of methylene chloride and methanol aseluent. There was thus obtained the title compound (0.13 g); NMRSpectrum: (CDCl₃) 1.86 (m, 2H), 2.47 (m, 6H), 3.6 (m, 2H), 3.7 (m, 4H),4.11 (s, 3H), 6.48 (d, 1H), 7.04-7.18 (m, 7H), 7.37 (m, 2H), 7.51 (s,1H), 8.02 (t, 1H), 8.65 (d, 1H), 9.19 (s, 1H); Mass Spectrum M+H⁺ 514.

The 4-chloro-7-methoxy-N-(3-morpholinopropyl)quinoline-6-carboxamideused as a starting material was prepared as follows:

A mixture of methyl 4-chloro-7-methoxyquinoline-6-carboxylate (3 g) andconcentrated aqueous hydrochloric acid (36%; 75 ml) was stirred andheated to 90° C. for 45 minutes. The mixture was allowed to cool toambient temperature, poured into water (150 ml) and washed withmethylene chloride. Evaporation of the aqueous phase gave4-chloro-7-methoxyquinoline-6-carboxylic acid hydrochloride (2.8 g); NMRSpectrum: (DMSOd₆) 3.98 (s, 3H), 7.6 (s, 1H), 7.7 (d, 1H), 8.4 (s, 1H),8.86 (d, 1H).

N-Hydroxybenzotriazole (0.235 g), triethylamine (1.8 ml),N-(3-aminopropyl)morpholine (2 ml) and1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (2.6 g) wereadded in turn to a mixture of the carboxylic acid so obtained and DMF(100 ml). The resultant reaction mixture was stirred at ambienttemperature for 16 hours. The mixture was partitioned between methylenechloride and a 10:1 mixture of water and methanol. The organic phase waswashed with a saturated aqueous sodium chloride solution, dried overmagnesium sulphate and evaporated. The resultant oil was purified bycolumn chromatography on silica using increasingly polar mixtures ofmethylene chloride and methanol as eluent. There was thus obtained therequired starting material (1.9 g); NMR Spectrum:—(CDCl₃) 1.87 (m, 2H),2.48 (m, 6H), 3.6 (m, 2H), 3.69 (m, 4H), 4.1 (s, 3H), 7.41 (d, 1H), 7.54(s, 1H), 7.99 (m, 1H), 8.74 (d, 1H), 9.01 (s, 1H); Mass Spectrum: M+H⁺363 & 365.

EXAMPLE 6

Using an analogous procedure to that described in Example 5, theappropriate 4-chloroquinoline-6-carboxamide was reacted with theappropriate phenol to give the compounds described in Table III.

TABLE III

No. (R⁴)_(n) R¹ Note  1 3,4-dichloro 3-morpholinopropyl (a)  23-dimethylamino 3-morpholinopropyl (b)  3 4-acetamido 3-morpholinopropyl(c)  4 4-methoxy 3-morpholinopropyl (d)  5 4-phenyl 3-morpholinopropyl(e)  6 4-methoxy 2-(2-oxoimidazolidin-1-yl)ethyl (f)  7 4-bromo3-morpholinopropyl (g)  8 3-bromo 3-morpholinopropyl (h)  9 4-nitro3-morpholinopropyl (i) 10 4-chloro 3-morpholinopropyl (j) 11 4-benzoyl3-morpholinopropyl (k) 12 3-cyano 3-morpholinopropyl (l) 13 4-cyano3-morpholinopropyl (m) 14 2-methoxy 3-morpholinopropyl (n) 15 3-methoxy3-morpholinopropyl (o) 16 4-phenoxy 2-(2-oxoimidazolidin-1-yl)ethyl (p)17 3-dimethylamino 2-(2-oxoimidazolidin-1-yl)ethyl (q) 18 3-methoxy2-(2-oxoimidazolidin-1-yl)ethyl (r) 19 2-methoxy2-(2-oxoimidazolidin-1-yl)ethyl (s) 20 3,4,5-trimethoxy2-(2-oxoimidazolidin-1-yl)ethyl (t) 21 3-cyano2-(2-oxoimidazolidin-1-yl)ethyl (u) 22 3-methoxy3-(2-oxopyrrolidin-1-yl)propyl (v) 23 2-fluoro-4-chloro2-dimethylaminoethyl (w) 24 3,4-dichloro 2-dimethylaminoethyl (x) 254-phenoxy 2-(2-pyridyl)ethyl (y) 26 4-methoxy 2-(2-pyridyl)ethyl (z) 273-morpholino 2-(2-pyridyl)ethyl (aa) 28 4-methylthio 2-(2-pyridyl)ethyl(bb) 29 3-phenoxy 2-(2-pyridyl)ethyl (cc) 30 3-phenoxy3-(1-imidazolyl)propyl (dd) 31 4-methylthio 3-(1-imidazolyl)propyl (ee)32 4-(3,5-diiodopyrid-4- 3-morpholinopropyl (ff) yloxy)

Notes

The product gave the following data: NMR Spectrum: (CDCl₃) 1.95 (broads, 2H), 2.61 (broad s, 6H), 3.61 (m, 2H), 3.78 (broad s, 4H), 4.13 (s,3H), 6.51 (d, 2H), 7.06 (m, 1H), 7.32 (d, 1H), 7.54 (m, 2H), 8.1 (broads, 1H), 8.69 (d, 1H), 9.13 (s, 1H); Mass Spectrum: M+H⁺ 491, 493 & 495.

The product gave the following data: NMR Spectrum: (CDCl₃) 1.86 (m, 2H),2.48 (m, 6H), 2.97 (s, 6H), 3.6 (m, 2H), 3.69 (m, 4H), 4.1 (s, 3H), 6.49(m, 2H), 6.54 (d, 1H), 6.63 (m, 1H), 7.27 (m, 1H), 7.48 (s, 1H), 8.01(t, 1H), 8.61 (d, 1H), 9.19 (s, 1H); Mass Spectrum: M+H⁺ 465.

The product gave the following data: NMR Spectrum: (CDCl₃) 1.81 (m, 2H),2.11 (s, 3H), 2.42 (m, 6H), 3.55 (m, 2H), 3.64 (m, 4H), 4.04 (s, 3H),6.34 (d, 1H), 6.95 (d, 2H), 7.44 (s, 1H), 7.65 (d, 2H), 8.11 (t, 1H),8.45 (s, 1H), 8.53 (d, 1H), 9.08 (s, 1H); Mass Spectrum: M+H⁺ 479.

(d) The product gave the following data: NMR Spectrum: (CDCl₃) 1.86 (m,2H), 2.49 (m, 6H), 3.6 (m, 2H), 3.7 (m, 4H), 3.85 (s, 3H), 4.1 (s, 3H),6.41 (d, 1H), 6.98 (d, 2H), 7.1 (d, 2H), 7.5 (s, 1H), 8.02 (m, 1H), 8.61(d, 1H), 9.19 (s, 1H); Mass Spectrum: M+H⁺ 452.

(e) The product gave the following data: NMR Spectrum: (CDCl₃) 1.87 (m,2H), 2.49 (m, 6H), 3.61 (q, 2H), 3.71 (m, 4H), 4.12 (s, 3H), 6.56 (d,1H), 7.34 (s, 1H), 7.72-7.34 (m, 9H), 8.06 (t, 1H), 8.66 (d, 1H), 9.22(s, 1H); Mass Spectrum: M+H⁺ 498.

(f) The product gave the following data: NMR Spectrum: (CDCl₃) 3.41-3.63(m, 6H), 3.7 (m, 2H), 3.86 (s, 3H), 4.12 (s, 3H), 4.33 (s, 1H), 6.41 (d,1H), 6.98 (d, 2H), 7.11 (d, 2H), 7.49 (s, 1H), 8.2 (m, 1H), 8.6 (d, 1H),9.24 (s, 1H); Mass Spectrum: M+H⁺ 437.

The4-chloro-7-methoxy-N-[2-(2-oxoimidazolidin-1-yl)ethyl]quinoline-6-carboxamideused as a starting material was prepared by the reaction of4-chloro-7-methoxyquinoline-6-carboxylic acid hydrochloride and2-(2-oxoimidazolidin-1-yl)ethylamine using an analogous procedure tothat described in the last paragraph of the portion of Example 5 whichis concerned with the preparation of starting materials. The requiredmaterial gave the following characterising data: NMR Spectrum: (CDCl₃)3.42-3.64 (m, 6H), 3.71 (m, 2H), 4.12 (s, 3H), 4.45 (m, 1H) 7.4 (d, 1H),7.53 (s, 1H), 8.19 (m, 1H), 8.74 (d, 1H), 9.08 (s, 1H); Mass Spectrum:M+H⁺ 349 & 351.

(g) The product gave the following data: NMR Spectrum: (CDCl₃) 1.85 (m,2H), 2.47 (m, 6H), 3.6 (q, 2H), 3.69 (m, 4H), 4.11 (s, 3H), 6.46 (d,1H), 7.06 (d, 2H), 7.52 (s, 1H), 7.57 (d, 2H), 8.02 (m, 1H), 8.65 (d,1H), 9.16 (s, 1H); Mass Spectrum: M+H⁺ 500 & 502.

(h) The product gave the following data: NMR Spectrum: (CDCl₃) 1.86 (m,2H), 2.51 (m, 6H), 3.61 (q, 2H), 3.7 (m, 4H), 4.11 (s, 3H), 6.5 (d, 1H),7.12 (m, 1H), 7.3 (m, 2H), 7.43 (m, 1H), 7.52 (s, 1H), 7.99 (m, 1H),8.65 (d, 1H), 9.16 (s, 1H); Mass Spectrum: M+H⁺ 500 & 502.

(i) The product gave the following data: NMR Spectrum: (CDCl₃) 1.88 (m,2H), 2.41-2.60 (broad s, 6H), 3.58 (m, 2H), 3.72 (broad s, 4H), 4.14(s,3H), 6.53 (d, 1H), 6.96 (m, 1H), 7.09 (d, 2H), 7.23 (d, 2H), 7.54 (s,2H), 8.05 (broad s, 1H), 8.25 (d, 2H), 8.68 (d, 1H), 9.19 (s, 1H); MassSpectrum: M+H⁺ 559.

(j) The product gave the following data: NMR Spectrum: (CDCl₃) 1.86 (m,2H), 2.48 (broad s, 6H), 3.6 (m, 2H), 3.71 (t, 4H), 4.11 (s, 3H), 6.48(d, 1H), 7.07 (d, 2H), 7.15 (d, 2H), 7.34 (d, 2H), 7.52 (s, 1H), 8.04(broad s, 1H), 8.65 (d, 1H), 9.19 (s, 1H); Mass Spectrum: M+H⁺ 548 &550.

(k) The product gave the following data: NMR Spectrum: (DMSOd₆) 1.77 (m,2H), 2.42 (broad s, 6H), 3.38 (m, 2H), 3.61 (t, 4H), 4.09(s, 3H), 6.85(d, 1H), 7.48 (d, 2H), 7.63 (d, 2H), 7.74 (m, 2H), 7.84 (d, 2H), 7.96(d, 2H), 8.44 (m, 1H), 8.55 (s, 1H), 881 (d, 1H); Mass Spectrum: M+H⁺526.

(l) The product gave the following data: NMR Spectrum: (CDCl₃) 1.86 (m,2H), 2.47 (broad m, 6H), 3.58 (m, 2H), 3.71 (t, 4H), 4.11 (s, 3H), 6.5(d, 1H), 7.45 (m, 2H), 7.56 (s, 1H), 7.62 (m, 2H), 8.05 (broad s, 1H),8.72 (d, 1H), 9.13 (s, 1H); Mass Spectrum: M+H⁺ 447.

(m) The product gave the following data: NMR Spectrum: (CDCl₃) 1.86 (m,2H), 2.48 (m, 6H), 3.59 (m, 2H), 3.71 (t, 4H), 4.13 (s, 3H), 6.58 (d,1H), 7.25 (d, 2H), 7.55 (s, 1H), 7.74 (d, 2H), 8.02 (broad s, 1H), 8.62(d, 1H), 9.09 (s, 1H); Mass Spectrum: M+H⁺ 447.

(n) The product gave the following data: NMR Spectrum: (CDCl₃) 1.87 (m,2H), 2.45 (broad m, 6H), 3.58 (m, 2H), 3.68 (t, 4H), 3.76 (s, 3H), 4.1(s, 3H), 6.32 (d, 1H), 7.05 (m, 2H), 7.17 (m, 1H), 7.3 (m, 1H), 7.41 (s,1H), 8.02 (broad s, 1H), 8.58 (d, 1H), 9.22 (s, 1H); Mass Spectrum: M+H⁺452.

(o) The product gave the following data: NMR Spectrum: (CDCl₃) 1.82 (m,2H), 2.46 (broad m, 6H), 3.62 (m, 2H), 3.72 (t, 4H), 3.84 (s, 3H), 4.1(s, 3H), 6.53 (d, 1H), 6.76 (m, 2H), 6.87 (m, 1H), 7.35 (t, 1H), 7.52(s, 1H), 8.03 (broad s, 1H), 8.64 (d, 1H), 9.17 (s, 1H), Mass Spectrum:M+H⁺ 452.

(p) The product gave the following data: NMR Spectrum: (CDCl₃) 3.42-3.62(m, 6H), 3.7 (m, 2H), 4.12 (s, 3H), 4.29 (s, 1H), 6.47 (d, 1H),7.01-7.17 (m, 7H), 7.38 (t, 2H), 7.5 (s, 1H), 8.21 (m, 1H), 8.64 (d,1H), 9.24 (s, 1H); Mass Spectrum: M+H⁺ 499.

(q) The product gave the following data: NMR Spectrum: (CDCl₃) 2.97 (s,6H), 3.41-3.61 (m, 6H), 3.7 (q, 2H), 4.12 (s, 3H), 4.27 (s, 1H),6.47-6.55 (m, 3H), 6.62 (m, 1H), 7.29 (m, 1H), 7.49 (s, 1H), 8.19 (m,1H), 8.61 (d, 1H), 9.25 (s, 1H); Mass Spectrum: M+H⁺ 450.

(r) The product gave the following data: NMR Spectrum: (CDCl₃) 3.42-3.52(m, 6H), 3.71 (m, 2H), 3.84 (s, 3H), 4.11 (s, 3H), 6.42-6.54 (m, 2H),6.73 (m, 1H), 6.85 (d, 1H), 7.11 (t, 1H), 7.34 (t, 1H), 7.49 (s, 1H),8.17 (broad s, 1H), 8.63 (d, 1H), 9.23 (s, 1H); Mass Spectrum: M+H⁺ 437.

(s) The product gave the following data: NMR Spectrum: (CDCl₃) 3.41-3.63(m, 6H), 3.7 (m, 2H), 3.76 (s, 3H), 4.12 (s, 3H), 4.31 (s, 1H), 6.32 (d,1H), 7.05 (m, 2H), 7.18 (d, 1H), 7.33 (m, 2H), 7.49 (s, 1H), 8.16 (broads, 1H), 8.58 (d, 1H), 9.28 (s, 1H); Mass Spectrum: M+H⁺ 437.

(t) The product gave the following data: NMR Spectrum: (CDCl₃) 3.43-3.63(m, 6H), 3.71 (q, 2H), 3.84 (s, 6H), 3.89 (s, 3H), 4.13 (s, 3H), 4.3 (s,1H), 6.43 (s, 2H), 6.53 (d, 1H), 7.5 (s, 1H), 8.19 (m, 1H), 8.65 (d,1H), 9.22 (s, 1H); Mass Spectrum: M+H⁺ 497.

(u) The product gave the following data: NMR Spectrum: (CDCl₃) 3.41-3.62(m, 6H), 3.72 (m, 2H), 4.12 (s, 3H), 4.38 (s, 1H), 6.48 (d, 1H), 7.14(m, 2H), 7.45 (m, 1H), 7.52 (s, 1H), 7.59 (d, 2H), 8.24 (broad s, 1H),8.7 (d, 1H), 9.13 (s, 1H); Mass Spectrum: M+H⁺ 432.

(v) The product gave the following data: NMR Spectrum: (CDCl₃) 1.86 (m,2H), 2.06 (m, 2H), 2.42 (t, 2H), 3.4-3.53 (m, 6H), 3.82 (s, 3H), 4.17(s, 3H), 6.5 (d, 1H), 6.71-6.79 (m, 2H), 6.84 (m, 1H), 7.35 (t, 1H),7.51 (s, 1H), 8.49 (m, 1H), 8.63 (d, 1H), 9.21 (s, 1H); Mass Spectrum:M+H⁺ 450.

The4-chloro-7-methoxy-N-[3-(2-oxopyrrolidin-1-yl)propyl]quinoline-6-carboxamide,used as a starting material, was prepared by the reaction of4-chloro-7-methoxyquinoline-6-carboxylic acid hydrochloride and3-(2-oxopyrrolidin-1-yl)propylamine using an analogous procedure to thatdescribed in the last paragraph of the portion of Example 5 which isconcerned with the preparation of starting materials. The requiredmaterial gave the following characterising data: Mass Spectrum: M+H⁺ 362& 364.

(w) The product gave the following data: NMR Spectrum: (CDCl₃) 2.35 (s,6H), 2.6 (m, 2H), 3.62 (q, 2H), 4.09 (s, 3H), 6.39 (d, 1H), 7.2-7.32 (m,3H), 7.5 (s, 1H), 8.37 (m, 1H), 8.65 (d, 1H), 9.22 (s, 1H); MassSpectrum: M+H⁺ 418 & 420.

The 4-chloro-7-methoxy-N-(2-dimethylaminoethyl)quinoline-6-carboxamide,used as starting material, was prepared by reaction of4-chloro-7-methoxyquinoline-6-carboxylic acid hydrochloride and2-dimethylaminoethylamine using an analogous procedure to that describedin the last paragraph of the portion of Example 5 which is concernedwith the preparation of starting materials. The required material gavethe following characterising data: NMR Spectrum: (CDCl₃) 2.35 (s, 6H),2.6 (t, 2H), 3.63 (q, 2H), 4.1 (s, 3H), 7.39 (d, 1H), 7.53 (s, 1H), 8.32(m, 1H), 8.73 (d, 1H), 9.06 (s, 1H); Mass Spectrum: M+H⁺ 308 & 310.

(x) The product gave the following data: NMR Spectrum: (CDCl₃) 2.38 (s,6H), 2.65 (t, 2H), 3.65 (q, 2H), 4.11 (s, 3H), 6.51 (d, 1H), 7.06 (m,1H), 7.32 (d, 1H), 7.53 (s, 1H), 7.55 (s, 1H), 8.39 (m, 1H), 8.68 (d,1H), 9.15 (s, 1H); Mass Spectrum: M+H⁺ 434 & 436.

(y) The product gave the following data: NMR Spectrum: (CDCl₃) 3.17 (t,2H), 3.97 (q, 2H), 4.0 (s, 3H), 6.47 (d, 1H), 7.04-7.21 (m, 9H), 7.38(m, 2H), 7.45 (s, 1H), 7.65 (m, 1H), 8.45 (m, 1H), 8.68 (m, 2H), 9.26(s, 1H); Mass Spectrum: M+H⁺ 492.

The 4-chloro-7-methoxy-N-[2-(2-pyridyl)ethyl]quinoline-6-carboxamide,used as starting material, was prepared by reaction of4-chloro-7-methoxyquinoline-6-carboxylic acid hydrochloride and2-(2-pyridyl)ethylamine using an analogous procedure to that describedin the last paragraph of the portion of Example 5 which is concernedwith the preparation of starting materials.

(z) The product gave the following data: NMR Spectrum: (CDCl₃) 3.17 (t,2H), 3.86 (s, 3H), 3.98 (q, 2H), 4.0 (s, 3H), 6.41 (d, 1H), 6.97 (d,2H), 7.1 (d, 2H), 7.15-7.29 (m, 2H), 7.45 (s, 1H), 7.65 (td, 1H), 8.43(m, 1H), 8.01 (d, 1H), 9.25 (s, 1H); Mass Spectrum: M+H⁺ 430.

(aa) The product gave the following data: NMR Spectrum: (CDCl₃) 3.19 (m,6H), 3.86 (m, 4H), 3.98 (q, 2H), 4.01 (s, 3H), 6.51 (d, 1H), 6.68 (d,2H), 6.83 (m, 1H), 7.16-7.28 (m, 2H), 7.34 (t, 1H), 7.47 (s, 1H), 7.65(m, 1H), 8.44 (m, 1H), 8.62 (d, 2H), 9.25 (s, 1H); Mass Spectrum: M+H⁺485.

(bb) The product gave the following data: NMR Spectrum: (CDCl₃) 2.53 (s,3H), 3.16 (t, 2H), 3.97 (q, 2H), 4.0 (s, 3H), 6.45 (d, 1H), 7.11 (d,2H), 7.19 (m, 2H), 7.35 (s, 2H), 7.46 (s, 1H), 7.65 (m, 1H), 8.44 (m,1H), 8.63 (m, 2H), 9.24 (s, 1H); Mass Spectrum: M+H⁺ 446.

(cc) The product gave the following data: NMR Spectrum: (CDCl₃) 3.16 (t,2H), 3.97 (q, 2H), 4.0 (s, 3H), 6.53 (d, 1H), 6.81 (t, 1H), 6.91 (m,2H), 7.06-7.23 (m, 6H), 7.36 (m, 2H), 7.45 (s, 1H), 7.65 (m, 1H), 8.43(m, 1H), 8.63 (m, 2H), 9.2 (s, 1H); Mass Spectrum: M+H⁺ 492.

(dd) The product gave the following data: NMR Spectrum: (CDCl₃) 2.17 (m,2H), 3.53 (q, 2H), 4.09 (t, 2H), 4.12 (s, 2H), 6.55 (d, 1H), 6.81 (t,1H), 6.92 (m, 2H), 7.0 (s, 1H), 7.07 (m, 3H), 7.15 (t, 1H), 7.38 (m,3H), 7.52 (d, 2H), 7.96 (m, 1H), 8.66 (d, 1H), 9.23 (s, 1H); MassSpectrum: M+H⁺ 495.

The4-chloro-7-methoxy-N-[3-(1-imidazolyl)propyl]quinoline-6-carboxamide,used as starting material, was prepared by reaction of4-chloro-7-methoxyquinoline-6-carboxylic acid hydrochloride and3-(1-imidazolyl)propylamine using an analogous procedure to thatdescribed in the last paragraph of the portion of Example 5 which isconcerned with the preparation of starting materials.

(ee) The product gave the following data: NMR Spectrum: (CDCl₃) 2.18 (m,2H), 2.53 (s, 3H), 3.54 (q, 2H), 4.1 (t, 2H), 4.13 (s, 2H), 6.47 (d,1H), 7.0 (s, 1H), 7.09 (s, 1H), 7.11 (d, 2H), 7.35 (d, 2H), 7.53 (s,1H), 7.55 (s, 1H), 7.98 (m, 1H), 8.64 (d, 1H), 9.26 (s, 1H); MassSpectrum: M+H⁺ 449.

(ff) The product gave the following data: NMR Spectrum: (CDCl₃) 1.86 (m,2H), 2.48 (m, 6H), 3.6 (m, 2H), 3.71(t, 4H), 4.11 (s, 3H), 6.47 (d, 1H),6.9 (d, 2H), 7.15 (d, 2H), 7.51 (s, 1H), 8.02 (broad s, 1H), 8.65 (d,1H), 8.88 (s, 2H), 9.17 (s, 1H).

The 4-hydroxyphenyl 2,6-diiodo-4-pyridyl ether, used as startingmaterial, was prepared as follows:

A mixture of 3,5-diiodo-4-pyridone (Liebig's Annalen, 1932, 494, 284; 20g), phosphorus pentachloride (12 g) and phosphoryl chloride (50 ml) wasstirred and heated to 130° C. for 6.5 hours. The mixture was cooled toambient temperature and added cautiously to a mixture of ice and water.The resultant precipitate was isolated, washed with water and dried.There was thus obtained 4-chloro-3,5-diiodopyridine (17 g), m.p.172-174° C.

Sodium hydride (50% suspension in mineral oil, 1.83 g) was washed withpetroleum ether (b.p. 40-60° C.) and DMF (25 ml) was added to theresidue. 4-Methoxyphenol (0.62 g) was added portionwise to the stirredsuspension and the resultant mixture was stirred at ambient temperaturefor 15 minutes. 4-Chloro-3,5-diiodopyridine (1.83 g) was added and themixture was stirred and heated to 110° C. for 5 minutes. The mixture wascooled to ambient temperature and water (200 ml) was added. Theresultant precipitate was isolated, dried and recrystallised frompetroleum ether (b.p. 80-100° C.). There was thus obtained the3,5-diiodo-4-pyridyl 4-methoxyphenyl ether (1.87 g), m.p. 133-135° C.

After suitable repetition of the previous reaction, a solution of borontribromide (5 g) in methylene chloride (19 ml) was added to a stirredsolution of 3,5-diiodo-4-pyridyl 4-methoxyphenyl ether (4.53 g) inmethylene chloride (135 ml). The resultant mixture was stirred atambient temperature for 16 hours. The mixture was quenched with waterand extracted with diethyl ether. The combined organic extracts werewashed with water and a saturated aqueous sodium chloride solution,dried over sodium sulphate and evaporated. The residue wasrecrystallised from aqueous methanol. There was thus obtained4-hydroxyphenyl 2,6-diiodo-4-pyridyl ether (2.3 g), m.p. 255-258° C.

EXAMPLE 74-(4-anilinophenoxy)-7-methoxy-N-(3-morpholinopropyl)quinoline-6-carboxamide

Aniline (0.03 ml) was added to a stirred mixture of4-(4-bromophenoxy)-7-methoxy-N-(3-morpholinopropyl)quinoline-6-carboxamide(0.132 g), caesium carbonate (0.23 g), palladium acetate (0.01 g),2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (0.055 g) and toluene (5 ml)and the reaction mixture was stirred and heated to stirred and heated to100° C. for 16 hours. The mixture was evaporated and the resultantresidue was partitioned between ethyl acetate and water. The organicphase was washed with a saturated aqueous sodium chloride solution anddried over magnesium sulphate. The residue was purified by columnchromatography on silica using increasingly polar mixtures of methylenechloride and methanol as eluent. There was thus obtained the titlecompound (0.103 g); NMR Spectrum: (CDCl₃) 1.86 (m, 2H), 2.49 (m, 6H),3.6 (q, 2H), 3.7 (m, 4H), 4.1 (s, 3H), 5.77 (s, 1H), 6.5 (d, 1H), 6.96(t, 1H), 7.04-7.17 (m, 6H), 7.3 (m, 2H), 7.5 (s, 1H), 8.02 (m, 1H), 8.63(d, 1H), 9.19 (s, 1H); Mass Spectrum: M+H⁺ 513.

EXAMPLE 8

Using an analogous procedure to that described in Example 7, theappropriate bromophenoxyquinoline-6-carboxamide was reacted with theappropriate amine or aniline to give the compounds described in TableIV.

TABLE IV

No. (R⁴)_(n) R¹ R² Note 1 4-(2-fluoro-4-chloroanilino)3-morpholinopropyl H (a) 2 4-(N-methylanilino) 3-morpholinopropyl H (b)3 3-(n-butylamino) 3-morpholinopropyl H (c) 43-(2-dimethylaminoethylamino) 3-morpholinopropyl H (d)

Notes

(a) The product gave the following data: NMR Spectrum: (CDCl₃) 1.86 (m,2H), 2.49 (m, 6H), 3.6 (q, 2H), 2.7 (m, 4H), 4.11 (s, 3H), 5.82 (m, 1H),6.48 (d, 1H), 7.03-7.24 (m, 7H), 7.51 (s, 1H), 8.03 (m, 1H), 8.64 (m,1H), 9.19 (s, 1H); Mass Spectrum: M+H⁺ 565.

(b) The product gave the following data: NMR Spectrum: (CDCl₃) 1.87 (m,2H), 2.49 (m, 6H), 3.34 (s, 3H), 3.6 (q, 2H), 3.71 (m, 4H), 4.09 (s,3H), 6.52 (d, 1H), 6.62 (m, 1H), 6.69 (m, 1H), 6.8 (m, 1H), 7.08 (t,1H), 7.15 (d, 2H), 7.21-7.38 (m, 3H), 7.48 (s, 1H), 8.01 (m, 1H), 8.62(d, 1H), 9.14 (s, 1H); Mass Spectrum: M+H⁺ 527.

(c) The product gave the following data: NMR Spectrum: (CDCl₃) 0.96 (t,3H), 1.43 (s, 2H), 1.63 (m, 2H), 1.85 (m, 2H), 2.54 (m, 6H), 2.09 (t,2H), 3.59 (q, 2H), 3.69 (m, 4H), 4.1 (s, 3H), 6.38 (m, 1H), 6.48 (m,2H), 6.55 (d, 1H), 7.21 (m, 2H), 7.5 (s, 1H), 8.0 (m, 1H), 8.61 (d, 1H),9.17 (s, 1H); Mass Spectrum: M+H⁺ 493.

(d) The product gave the following data: NMR Spectrum: (CDCl₃) 1.85 (m,2H), 2.25 (s, 6H), 2.49 (m, 6H), 2.55 (t, 2H), 3.11 (m, 2H), 3.6 (q,2H), 3.69 (m, 4H), 4.1 (s, 3H), 4.49 (broad s, 1H), 6.4 (m, 1H), 6.46(d, 1H), 6.53 (m, 2H), 7.21 (t, 1H), 7.49 (s, 1H), 8.0 (m, 1H), 8.62 (d,1H), 9.16 (s, 1H); Mass Spectrum: M+H⁺ 508.

EXAMPLE 9 Pharmaceutical Compositions

The following illustrate representative pharmaceutical dosage forms ofthe invention as defined herein (the active ingredient being termed“Compound X”), for therapeutic or prophylactic use in humans:

(a) Tablet I mg/tablet Compound X 100 Lactose Ph.Eur 182.75Croscarmellose sodium 12.0 Maize starch paste (5% w/v paste) 2.25Magnesium stearate 3.0 (b) Tablet II mg/tablet Compound X 50 LactosePh.Eur 223.75 Croscarmellose sodium 6.0 Maize starch 15.0Polyvinylpyrrolidone (5% w/v paste) 2.25 Magnesium stearate 3.0 (c)Tablet III mg/tablet Compound X 1.0 Lactose Ph.Eur 93.25 Croscarmellosesodium 4.0 Maize starch paste (5% w/v paste) 0.75 Magnesium stearate 1.0(d) Capsule mg/capsule Compound X 10 Lactose Ph.Eur 488.5 Magnesium 1.5(e) Injection I (50 mg/ml) Compound X  5.0% w/v 1 M Sodium hydroxidesolution 15.0% v/v 0.1 M Hydrochloric acid (to adjust pH to 7.6)Polyethylene glycol 400  4.5% w/v Water for injection to 100% (f)Injection II (10 mg/ml) Compound X  1.0% w/v Sodium phosphate BP  3.6%w/v 0.1 M Sodium hydroxide solution 15.0% v/v Water for injection to100% (g) Injection III (1 mg/ml, buffered to pH6) Compound X  0.1% w/vSodium phosphate BP 2.26% w/v Citric acid 0.38% w/v Polyethylene glycol400  3.5% w/v Water for injection to 100% (h) Aerosol I mg/ml Compound X10.0 Sorbitan trioleate 13.5 Trichlorofluoromethane 910.0Dichlorodifluoromethane 490.0 (i) Aerosol II mg/ml Compound X 0.2Sorbitan trioleate 0.27 Trichlorofluoromethane 70.0Dichlorodifluoromethane 280.0 Dichlorotetrafluoroethane 1094.0 (j)Aerosol III mg/ml Compound X 2.5 Sorbitan trioleate 3.38Trichlorofluoromethane 67.5 Dichlorodifluoromethane 1086.0Dichlorotetrafluoroethane 191.6 (k) Aerosol IV mg/ml Compound X 2.5 Soyalecithin 2.7 Trichlorofluoromethane 67.5 Dichlorodifluoromethane 1086.0Dichlorotetrafluoroethane 191.6 (l) Ointment ml Compound X   40 mgEthanol 300 μl Water 300 μl 1-Dodecylazacycloheptan-2-one  50 μlPropylene glycol to 1 ml 

Note

The above formulations may be obtained by conventional procedures wellknown in the pharmaceutical art. The tablets (a)-(c) may be entericcoated by conventional means, for example to provide a coating ofcellulose acetate phthalate. The aerosol formulations (h)-(k) may beused in conjunction with standard, metered dose aerosol dispensers, andthe suspending agents sorbitan trioleate and soya lecithin may bereplaced by an alternative suspending agent such as sorbitan monooleate,sorbitan sesquioleate, polysorbate 80, polyglycerol oleate or oleicacid.

What is claimed is:
 1. A quinoline compound of the Formula I

wherein n is 0, 1, 2 or 3 and each R⁴, which may be the same or different, is halogeno, hydroxy, amino, nitro, trifluoromethyl, trifluoromethoxy, cyano, (1-6C)alkyl, (2-6C)alkenyl, (2-6C)alkynyl, (1-6C)alkoxy, (1-6C)alkylamino, di-[(1-6C)alkyl]amino, (2-6C)alkanoylamino, (1-6C)alkylthio, (1-6C)alkylsulphinyl, (1-6C)alkylsulphonyl, pyrrolidin-1-yl, piperidino, morpholino, piperazin-1-yl or 4-(1-6C)alkylpiperazin-1-yl, and any CH₂ or CH₃ group in a R⁴ group optionally bears on each such CH₂ or CH₃ group a substituent selected from halogeno, hydroxy, amino, cyano, (1-6C)alkyl, (1-6C)alkoxy, (1-6C)alkylamino, di-[(1-6C)alkyl]amino and (2-6C)alkanoylamino, or R⁴ is phenyl, phenoxy, anilino, N-(1-6C)alkylanilino, benzoyl, phenylthio, phenylsulphinyl, phenylsulphonyl, benzyl, pyridyl or pyridyloxy and the phenyl or pyridyl group in any of the 11 last-named substituents is optionally substituted with 1, 2 or 3 substituents, which may be the same or different, selected from halogeno, hydroxy, amino, nitro, trifluoromethyl, trifluoromethoxy, cyano, (1-6C)alkyl, (2-6C)alkenyl, (2-6C)alkynyl, (1-6C)alkoxy, (1-6C)alkylamino, di-[(1-6C)alkyl]amino and (2-6C)alkanoylamino, or (R⁴)_(n) is a (1-3C)alkylenedioxy substituent; R¹ is hydrogen, (1-6C)alkyl, (2-6C)alkenyl or (2-6C)alkynyl; R² is hydrogen, (1-6C)alkyl, (2-6C)alkenyl or (2-6C)alkynyl; and wherein any CH₂ or CH₃ group in an R¹ or R² group optionally bears on each such CH₂ or CH₃ group a substituent selected from halogeno, hydroxy, amino, cyano, carbamoyl, sulphamoyl, (1-6C)alkoxy, (1-6C)alkylamino, di-[(1-6C)alkyl]amino, (2-6C)alkanoylamino, (1-6C)alkylthio, (1-6C)alkylsulphinyl, (1-6C)alkylsulphonyl, N-(1-6C)alkylcarbamoyl, N,N-di-[(1-6C)alkyl]carbamoyl, N-(1-6C)alkylsulphamoyl and N,N-di-[(1-6C)alkyl]sulphamoyl, or a substituent selected from aryl, aryloxy, arylamino, N-(1-6C)alkyl-arylamino, aryl-(1-6C)alkoxy, aryl-(1-6C)alkylamino, N-(1-6C)alkyl-aryl-(1-6C)alkylamino, aroylamino, N-arylcarbamoyl, aryl-(2-6C)alkanoylamino and N-[aryl-(1-6C)alkyl]carbamoyl, or a substituent selected from (3-7C)cycloalkyl, (3-7C)cycloalkyloxy, (3-7C)cycloalkylamino, N-(1-6C)alkyl-(3-7C)cycloalkylamino, (3-7C)cycloalkyl-(1-6C)alkoxy, (3-7C)cycloalkyl-(1-6C)alkylamino, N-(1-6C)alkyl-(3-7C)cycloalkyl-(1-6C)alkylamino, (3-7C)cycloalkylcarbonylamino, N-[(3-7C)cycloalkyl]carbamoyl, (3-7C)cycloalkyl-(2-6C)alkanoylamino and N-[(3-7C)cycloalkyl-(1-6C)alkyl]carbamoyl, or a substituent selected from heteroaryl, heteroaryloxy, heteroarylamino, N-(1-6C)alkyl-heteroarylamino, heteroaryl-(1-6C)alkoxy, heteroaryl-(1-6C)alkylamino, N-(1-6C)alkyl-heteroaryl-(1-6C)alkylamino, heteroarylcarbonylamino, N-heteroarylcarbamoyl, heteroaryl-(2-6C)alkanoylamino and N-[heteroaryl-(1-6C)alkyl]carbamoyl, or a substituent selected from heterocyclyl, heterocyclyloxy, heterocyclylamino, N-(1-6C)alkyl-heterocyclylamino, heterocyclyl-(1-6C)alkoxy, heterocyclyl-(1-6C)alkylamino, N-(1-6C)alkyl-heterocyclyl-(1-6C)alkylamino, heterocyclylcarbonylamino, N-heterocyclylcarbamoyl, heterocyclyl-(2-6C)alkanoylamino and N-[heterocyclyl-(1-6C)alkyl]carbamoyl, and wherein any aryl, (3-7C)cycloalkyl, heteroaryl or heterocyclyl group in a substituent on R¹ or R² optionally bears 1, 2 or 3 substituents, which may be the same or different, selected from halogeno, hydroxy, amino, nitro, trifluoromethyl, trifluoromethoxy, cyano, (1-6C)alkyl, (2-6C)alkenyl, (2-6C)alkynyl, (1-6C)alkoxy, (1-6C)alkylamino, di-[(1-6C)alkyl]amino and (2-6C)alkanoylamino and any (3-7C)cycloalkyl or heterocyclyl group on a R¹ or R² group optionally bears 1 or 2 oxo substituents; and R³ is hydrogen, halogeno, hydroxy, amino, (1-6C)alkyl, (1-6C)alkoxy, (1-6C)alkylamino, di-[(1-6C)alkyl]amino or (2-6C)alkanoylamino; or a pharmaceutically-acceptable salt thereof.
 2. A quinoline compound of the Formula I according to claim 1 wherein n is 1, 2 or 3 and each R⁴ group is independently selected from fluoro, chloro, bromo, hydroxy, amino, trifluoromethyl, methyl, methoxy, methylamino, dimethylamino, acetamido, phenyl and phenoxy and wherein said 2 last-named substituents optionally bear 1, 2 or 3 substituents selected from fluoro, chloro, bromo, methyl and methoxy; R² is hydrogen; R¹ is ethyl, propyl or butyl which bears 1 or 2 substituents selected from hydroxy, amino, cyano, methoxy, ethoxy, methylamino, ethylamino, dimethylamino, diethylamino, acetamido, phenyl, imidazolyl, pyridyl, pyrrolidinyl, imidazolidinyl, morpholinyl, piperidinyl and piperazinyl and wherein any of the 8 last-named substituents on R¹ optionally bears 1 or 2 further substituents selected from fluoro, chloro, bromo, hydroxy, amino, trifluoromethyl, cyano, methyl, methoxy, methylamino, dimethylamino and acetamido and wherein any of the pyrrolidinyl, imidazolidinyl, morpholinyl, piperidinyl and piperazinyl substituents on R¹ optionally bears 1 or 2 oxo substituents; and R³ is methoxy; or a pharmaceutically-acceptable salt thereof.
 3. A quinoline compound of the Formula I according to claim 1 wherein n is 1, 2 or 3 and each R⁴ group is independently selected from fluoro, chloro, bromo, hydroxy, amino, trifluoromethyl, cyano, methyl, ethyl, methoxy, ethoxy, methylamino, ethylamino, propylamino, butylamino, dimethylamino, diethylamino, acetamido, methylthio, piperidin-1-yl, piperidino, morpholino, piperazin-1-yl, 4-methylpiperazin-1-yl, phenyl, phenoxy, anilino, N-methylanilino, benzoyl, phenylthio, benzyl, 4-pyridyl and 4-pyridyloxy; R² is hydrogen; R¹ is ethyl, propyl or butyl which bears a substituent selected from hydroxy, amino, methoxy, methylamino, dimethylamino, acetamido, methylthio, methylsulphinyl, methylsulphonyl, N-methylcarbamoyl, N,N-dimethylcarbamoyl, N-methylsulphamoyl, N-ethylsulphamoyl, N-propylsulphamoyl, N,N-dimethylsulphamoyl, 4-chlorophenyl, 4-aminophenyl, 4-methoxyphenyl, 1-imidazolyl, 2-imidazolyl, 2-pyridyl, pyrrolidin-1-yl, 2-oxopyrrolidin-1-yl, 2-oxoimidazolidin-1-yl, 2,4-dioxoimidazolidin-1-yl, 5-methyl-2,4-dioxothiazolidin-3-piperidino, 2,6-dioxopiperidin-1-yl, morpholino, piperazin-1-yl and 4-methylpiperazin-1-yl; and R³ is methoxy; or a pharmaceutically-acceptable salt thereof.
 4. A quinoline compound of the Formula I according to claim 1 wherein n is 1 or 2 and each R⁴ group is independently selected from fluoro, chloro, dimethylamino, acetamido, phenyl and phenoxy; R² is hydrogen; R¹ is ethyl or propyl which bears a substituent selected from 4-chlorophenyl, 4-aminophenyl, 4-methoxyphenyl, 2-pyridyl, 2-oxoimidazolidin-1-yl and morpholino; and R³ is methoxy; or a pharmaceutically-acceptable salt thereof.
 5. A quinoline compound of the Formula I according to claim 1 selected from: 4-(4-chloro-2-fluorophenoxy)-7-methoxy-N-(3-morpholinopropyl)quinoline-6-carboxamide, 4-(3,4-dichlorophenoxy)-7-methoxy-N-(3-morpholinopropyl)quinoline-6-carboxamide, 4-(4-chloro-2-fluorophenoxy)-N-[2-(2-oxoimidazolidin-1-yl)ethyl]-7-methoxyquinoline-6-carboxamide and 7-methoxy-N-(3-morpholinopropyl)-4-(4-phenoxyphenoxy)quinoline-6-carboxamide; or a pharmaceutically-acceptable salt thereof.
 6. A process for the preparation of a quinoline compound of the Formula I, or a pharmaceutically-acceptable salt thereof, according to claim 1 which comprises (a) the reaction of a quinoline of the Formula II

wherein Z is a displaceable group and R¹, R², R³ and m have any of the meanings defined in claim 1 except that any functional group is protected if necessary, with a phenol of the Formula III

wherein R⁴ and n have any of the meanings defined in claim 1 except that any functional group is protected if necessary, whereafter any protecting group that is present is removed by conventional means; (b) the reaction of a carboxylic acid of the Formula VII, or a reactive compound thereof,

wherein R³, R⁴ and n have any of the meanings defined in claim 1 except that any functional group is protected if necessary, with an amine of the Formula V

wherein R¹ and R² have any of the meanings defined in claim 1 except that any functional group is protected if necessary, whereafter any protecting group that is present is removed by conventional means; (c) for the preparation of those compounds of the Formula I wherein R⁴ is an amino, (1-6C)alkylamino, di-[(1-6C)alkyl]amino, anilino or N-(1-6C)alkylanilino group, the reaction of a compound of the Formula VIII wherein R¹, R² and R³ have any of the meanings defined in claim 1 except that any functional group is protected if necessary and Z is a displaceable group,

with an amine or aniline as appropriate whereafter any protecting group that is present is removed by conventional means; and when a pharmaceutically-acceptable salt of a quinoline compound of the Formula I is required it may be obtained by reaction of said quinoline compound with a suitable acid using a conventional procedure.
 7. A pharmaceutical composition which comprises a quinoline compound of the Formula I, or a pharmaceutically-acceptable salt thereof, as defined in claim 1 in association with a pharmaceutically-acceptable diluent or carrier.
 8. A method for the prevention or treatment of an autoimmune disease or medical condition in a warm-blooded animal in need thereof which comprises administering to said animal an effective amount of a quinoline compound of the Formula I, or a pharmaceutically-acceptable salt thereof, as defined in claim
 1. 9. A method for producing an anti-inflammatory effect in a warm blooded animal in need thereof which comprises administering to said animal an effective amount of a compound of the Formula I, or a pharmaceutically-acceptable salt thereof, as claimed in claim
 1. 10. A method for treating an inflammatory disease or medical condition in a warm blooded animal in need thereof, which comprises administering to said animal an effective amount of a compound of the Formula I, or a pharmaceutically-acceptable salt thereof, as claimed in claim
 1. 11. The method of claim 10 wherein said inflammatory disease or medical condition is selected from rheumatoid arthritis, inflammatory bowel disease, glomerulonephritis and lung fibrosis.
 12. A method of treating or preventing acute rejection of a transplanted organ or tissue is a warm blooded animal, which comprises administering to said animal an effective amount of a compound of the Formula I, or a pharmaceutically-acceptable salt thereof, as claimed in claim
 1. 13. A method for producing an immunoregulatory or immunosuppressive effect in a warm blooded animal in need thereof for the prevention or treatment of tissue or organ rejection following transplant surgery, which comprises administering to said animal an effective amount of a compound of the Formula I, or a pharmaceutically-acceptable salt thereof, as claimed in claim
 1. 14. A method of limiting T cell activation in a warm blooded animal in need thereof by inhibition of at least one tyrosine-specific protein kinase involved in early signal transduction, which comprises administering to said animal an effective amount of a compound of the Formula I, or a pharmaceutically-acceptable salt thereof, as claimed in claim
 1. 15. The method of claim 14 wherein at least one said tyrosine-specific protein kinase is P56^(lck). 